Substituted nitrogen containing compounds

ABSTRACT

each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3a, R3b, L1, B, V, Y, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application U.S. patent applicationSer. No. 16/679,435, filed, Nov. 11, 2019, which is a continuation ofU.S. patent application Ser. No. 15/993,683, filed May 31, 2018, nowU.S. Pat. No. 10,501,449, which claims the benefit of Indian ProvisionalApplication No. 201811004486, filed Feb. 6, 2018 and Indian ProvisionalApplication No. 201711019293, filed Jun. 1, 2017, the contents of whichare specifically incorporated by reference herein.

The present invention generally relates to substituted nitrogencontaining heterocyclic compounds useful as inhibitors of ROMK channelactivity. Provided herein are substituted nitrogen containing compounds,compositions comprising such compounds, and methods of their use. Theinvention further pertains to pharmaceutical compositions containing atleast one compound according to the invention that are useful for thetreatment of conditions related to ROMK channel activity, includingcardiovascular diseases.

BACKGROUND

The renal outer medullary potassium (ROMK, Kir1.1) channel is a weakinward rectifying K⁺ channel with a key role in renal K⁺ recycling andsecretion (Ho et al., Nature, 1993, 362, 31-38; Shuck et al., TheJournal of Biological Chemistry, 1994, 269(39), 24261-24270; Lee andHebert, American Journal of Physiology-Renal Physiology, 1995, 268(6),F1124-F1131; Lu et al., The Journal of Biological Chemistry, 2002, 277,37881-37887; and Hebert et al., Physiological Reviews, 2005,85:319-371). In the thick ascending limb (TAL) of a nephron, ROMKchannel activity provides the K⁺ gradient necessary for Na and Clreabsorption by the Na⁺—K⁺-2Cl⁻ (NKCC2) co-transporter. In the distalconvoluted tubule (DCT) and cortical collecting duct (CCD), ROMKchannels form the major secretory pathway for K⁺ and as a result, playan important role in K⁺ homeostasis under physiological conditions(Welling and Ho, American Journal of Physiology-Renal Physiology, 2009,297(4): F849-F863).

Multiple lines of evidence indicate that inhibition of ROMK channelactivity results in natriuresis, diuresis and reduced blood pressure.Therefore, ROMK inhibition may offer a novel mechanism of blood pressureregulation and diuresis in patients suffering from hypertension,congestive heart failure or any other edematous disease conditions. Theactivity of NKCC2 transporter is tightly coupled with ROMK activity inthe TAL region and homozygous loss of function mutations in ROMK inhumans result in a disease phenotype (renal salt wasting, increasedaldosterone levels, metabolic alkalosis, reduction in blood pressure)very similar to that of NKCC2 homozygous mutations but with a milderhypokalemia (Simon et al., Nature Genetics, 1996, 14: 152-156). Inaddition, humans identified with heterozygous ROMK mutations from theFramingham Heart Study presented with reduced blood pressure (Ji et al.,Nature Genetics, 2008, 40(5): 592-599). Similar to human genetics, mousegenetics also support the role of ROMK in Na⁺ reabsorption in the kidneyand overall blood pressure regulation (Lu et al., The Journal ofBiological Chemistry, 2002, 277, 37881-37887; and Lorenz et al., TheJournal of Biological Chemistry, 2002, 277: 37871-37880). Furthermore,pharmacological blockade of the ROMK channel has been shown to inducenatriuresis and diuresis in rats upon acute dosing and in dogs upon bothacute and prolonged dosing (Tang et al., Bioorganic and MedicinalChemistry Letter, 2013, 23: 5829-5832; Garcia et al., The Journal ofPharmacology and Experimental Therapeutics, 2014, 348: 153-164; Walsh etal., ACS Medicinal Chemistry Letters, 2015, 6: 747-752; and Dajee etal., Circulation, 2014, 130: A12397). Since the ROMK channel is alsoimplicated in regulation of net K⁺ secretion in the distal part of thenephron, it is believed that ROMK inhibition in this region willmitigate the K⁺ wasting and hypokalemia associated with loop andthiazide diuretics. Acute or prolonged (up to 122 days) ROMK antagonismdoes not lead to kaliuresis or hypokalemia in dogs (Garcia et al., TheJournal of Pharmacology and Experimental Therapeutics, 2014, 348:153-164; Walsh et al., ACS Medicinal Chemistry Letters, 2015, 6:747-752; Dajee et al., Circulation, 2014, 130: A12397). Together, thesedata suggest that inhibition of ROMK may produce diuretic efficacy thatis equivalent to or better than currently available loop diuretics andwith potentially lower incidence of hypokalemia.

WO 2015/095097 discloses compounds useful as inhibitors of ROMK. Otherpublications disclosing compounds useful as inhibitors of ROMK includeWO 2010/129379, WO 2010/136144, WO 2012/058116, WO 2012/058134, WO2013/028474, WO 2013/039802, WO 2013/062892, WO 2013/062900, WO2013/066714, WO 2013/066717, WO 2013/066718, WO 2013/090271, WO2014/015495, WO 2014/018764, WO 2014/085210, WO 2014/099633, WO2014/126944, WO 2014/150132, WO 2015/017305, WO 2015/065866, WO2015/095097, WO 2015/100147, WO 2015/105736, WO 2016/008064, WO2016/010801, WO 2016/010802, WO2016/060941, WO2016/065582,WO2016/065602, WO2016/065603, WO2016/069426, WO2016/069427,WO2016/069428, WO2016/069430, WO2016/091042, WO2016/122994,WO2016/127358, WO2016/130444, CN105693706, and WO2016/091042.

In view of the numerous conditions that are contemplated to benefit bytreatment involving inhibition of ROMK, it is immediately apparent thatnew compounds capable of inhibiting ROMK and methods of using thesecompounds should provide substantial therapeutic benefits to a widevariety of patients.

The present invention relates to a new class of compounds found to beeffective inhibitors of ROMK.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that are usefulas inhibitors of ROMK, and are useful for the treatment ofcardiovascular diseases and promotion of diuresis or natriuresis.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of Formula (I) or stereoisomers, tautomers, salts,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides a method for inhibiting ROMKcomprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds ofFormula (I) or stereoisomers, tautomers, salts, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating cardiovasculardisease comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds ofFormula (I) or stereoisomers, tautomers, salts, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating cardiovasculardisease comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds ofFormula (I) or stereoisomers, tautomers, salts, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, either alone or incombination with other compounds of the present invention, or incombination with one or more other agent(s). One embodiment provides amethod for treating cardiovascular disease. Particular, cardiovasculardiseases include, but are not limited to, hypertension, coronary heartdisease, stroke, heart failure, systolic heart failure, diastolic heartfailure, diabetic heart failure, acute-decompensated heart failure,post-operative volume overload, idiopathic edema, pulmonaryhypertension, pulmonary arterial hypertension, cardiac insufficiency,nephrotic syndrome, and acute kidney insufficiency.

One embodiment provides a method for promotion of diuresis ornatriuresis.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of cardiovascular disease or promotion ofdiuresis or natriuresis. The present invention also provides a compoundof Formula (I) or a pharmaceutical composition in a kit withinstructions for using the compound or composition.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

These and other features of the invention will be set forth furtherbelow.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formula (I):

or stereoisomer, tautomer, salt, pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein:

-   R¹ is:

-   each W is independently NR^(1b) or O;-   Z is a bond or CHR^(1d);-   X is independently N or CR^(1a), wherein X is N at only 0, 1, or 2    positions;-   each R^(1a) is independently H, F, Cl, —OH, —CN, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy, or C₁₋₃ fluoroalkoxy;-   each R^(1b) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆    cycloalkyl-   R^(1c) is independently H, deuterium, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,    or C₃₋₆ cycloalkyl;-   R^(1d) is H, C₁₋₃ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl;-   Y is —C(R⁶)₂—, —C(R⁶)₂—C(R⁶)₂—, —C(═O)—, —C(═O)—C(R⁶)₂—,    —C(R⁶)₂—C(═O)—, or —SO₂—;-   V is —O—, —NR⁴—, —CR⁵R⁵—, —S—, —S(O)—, —SO₂—, or —C(═O)—; wherein if    V is —O—, —S—, —S(O)—, —SO₂—, or —C(═O)—, then Y is not —SO₂—, and    wherein if V is —O—, —S—, or NR⁴, then Y is not C(R⁶)₂, and wherein    if V is —S(O)—, —SO₂—, or C(═O)—, then Y is not —C(═O)—,    —C(═O)—C(R⁶)₂—;-   L¹ is —C(R)₂—, —C(═O)—, or —C(R)₂—C(R)₂—; wherein R is independently    H, F, OH, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃    fluoroalkyl; wherein R is not —OH or F if it is attached to a carbon    atom that is adjacent to a nitrogen atom:-   Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, thiazolyl,    imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,    isoxazolyl, isothiazolyl, pyrrolyl, pyrazinyl, oxazolyl,    pyridazinyl, pyrrolidinyl, or imidazolidinyl,-   R² is a C₆₋₁₀ aryl, or a 5 to 10 membered heterocycle ring    containing 1 to 4 heteroatoms selected from N, O, and S, the    heterocycle optionally containing an oxo substitution, the aryl or    heterocycle are substituted with 0-3 R^(2a);-   R^(2a) is independently OH, ═O, CN, halo, C₁₋₄ alkyl, C₁₋₄    deuteroalkyl, C₁₋₄ fluoroalkyl, C₁₋₄ alkoxy, C₁₋₄ deuteroalkoxy,    C₁₋₄ fluoroalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy,    C(═O)N(R^(4b)R^(4b)), C(═O)CM alkyl, SO₂R^(e), NR^(4b)SO₂R^(4b), or    a 4 to 6 membered heterocycle having 1, 2, 3, or 4 heteroatoms    selected from O, S, and N, the heterocycle optionally containing an    oxo substitution and is substituted with 0-3 R^(2b);-   R^(2b) is independently C₁₋₃ alkyl C₁₋₃ fluoralkyl, C₁₋₃    hydroxyalkyl, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl;-   R^(3a) is H, halo, OH, CN, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃    fluoroalkyl, C₁₋₃ alkoxy, or C₃₋₆ cycloalkyl, wherein if V is —O—,    —NR⁴—, —S—, —S(O)—, —SO₂—, or —C(═O)—, then R^(3a) is not halo,    wherein if V is —O—, —NR⁴—, —S—, then R^(3a) is not OH, CN;-   R^(3b) is H, ═O, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkyl,    C₁₋₃ alkoxy, or C₃₋₆ cycloalkyl;-   R⁴ is H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₂₋₃ hydroxyalkyl, CO₂R^(4a),    C(═O)R^(4a), SO₂R^(4a), C(═O)N(R^(4b)R^(4b)), SO₂N(R^(4b)R^(4b)), or    OH;-   R^(4a) is C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, C₆₋₁₀ aryl or a 4 to 10 membered heterocycle    having 1, 2, 3 or 4 heteroatoms selected from O, S, and N, the aryl    or heterocycle being substituted with 0-3 R^(4c);-   R^(4b) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆    cycloalkyl, C₃₋₆ fluorocycloalkyl, C₆₋₁₀ aryl or a 4 to 10 membered    heterocycle having 1, 2 3 or 4 heteroatoms selected from O, S, N;-   alternatively, 2 R^(4b)'s, along with the atom to which they are    attached, join to form a 3 to 6 membered saturated ring containing    an additional 0-2 heteroatoms selected from O, S, and N;-   R^(4c) is independently H, F, Cl, or C₁₋₃ alkyl;-   R⁵ is independently H, F, OH, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, C₁₋₃    alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, NR^(5b)R^(5b), or O—R^(5c), or 2 R⁵s are ═O;    wherein if one R⁵ is F, OH or NR^(5b)R^(5b), then the other R⁵ is    not OH, or NR^(5b)R^(5b).-   R^(5b) is independently H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C(O)R^(a),    SO₂R^(a) or C(O)NR^(b)R^(b); alternatively, 2 R^(5b)'s, along with    the atom to which they are attached, join to form a 3 to 6 membered    saturated ring containing 0-2 heteroatoms selected from O, S, or N;-   R^(5c) is independently H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, or    C(O)NR^(b)R^(b);-   R⁶ is independently H, OH, F, C₁₋₃ alkyl, C₁₋₃ deuteroalkyl, C₁₋₃    fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl, C₁₋₃ alkoxy,    C₁₋₃ hydroxyalkyl, C₁₋₃ hydroxydeuteroalkyl, C₁₋₃ alkoxyalkyl, or    C₁₋₃ fluoroalkoxyalkyl, or NR^(6b)R^(6b); wherein if one R⁶ on one    carbon atom is F, OH or NR^(6b)R^(6b), then the other R⁶ on the same    carbon atom is not OH or NR^(6b)R^(6b).-   R^(6b) is independently H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C(O)R^(a),    SO₂R^(a) or C(O)NR^(b)R^(b); alternatively, 2 R⁶s along with the    same atom to which they are attached can form a 3 to 6 membered    saturated ring containing 0-2 heteroatoms selected from O, S, and N;-   R^(a) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆    cycloalkyl, C₃₋₆ fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered    heterocycle having 1, 2, 3, or 4 heteroatoms selected from O, S, and    N;-   R^(b) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆    cycloalkyl, C₃₋₆ fluorocycloalkyl, C₆₋₁₀ aryl or a 4 to 10 membered    heterocycle having 1, 2 3 or 4 heteroatoms selected from O, S, and    N;-   alternatively, 2 R^(b)'s along with the atom to which they are    attached, join to form a 3-6 membered saturated ring, containing 0-2    heteroatoms selected from O, S, and N;-   each R^(d) is independently H, F, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃    alkoxy, C₁₋₃ fluoroalkoxy, C₁₋₃ hydroxyalkyl, C₃₋₆ cycloalkyl, halo,    OH, ═O, CN, OCF₃, OCHF₂, CHF₂CF₃. or C(O)NR^(e)R^(e);-   each R^(e) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆    cycloalkyl, C₂₋₃ hydroxyalkyl, C₂₋₃ alkoxyalkyl, C₆₋₁₀ aryl, or a 5    to 10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected    from O, S, and N;-   alternatively, 2 R^(e)'s along with the atom to which they are    attached, join to form a 3 to 6 membered saturated ring, containing    0-2 heteroatoms selected from O, S, and N; and-   n is 0, 1, or 2.

The another aspect of the present invention provides at least onecompound of Formula (I):

or stereoisomer, tautomer, salt, pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein:

-   R¹ is:

-   each W is independently NR^(1b) or O;-   Z is a bond or CHR^(1d);-   X is N or CR^(1a), wherein X is N at only 0, 1, or 2 positions;-   each R^(1a) is independently H, F, Cl, —OH, —CN, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy, or C₁₋₃ fluoroalkoxy;-   each R^(1b) is independently H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, or    C₃₋₆ cycloalkyl;-   R^(1c) is H, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl;-   R^(1d) is H, C₁₋₃ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl;-   V is —O—, —NR⁴—, —CR⁵R⁵—, —S—, —S(O)—, —SO₂—, or —C(═O)—; wherein if    V is —O—, —S—, —S(O)—, —SO₂—, or —C(═O)—, then Y is not —SO₂, and    wherein if V is —O—, —S—, or NR⁴, then Y is not C(R⁶)₂;-   Y is —C(R⁶)₂—, —C(R⁶)₂—C(R⁶)₂—, —C(═O)—, —C(═O)—C(R⁶)₂—,    —C(R⁶)₂—C(═O)—, or —SO₂—;-   L¹ is —C(R)₂—, —C(═O)—, —C(R)₂—CH₂—, —CH₂—C(R)₂—, or —C(R)₂—C(R)₂;    wherein R is independently hydrogen, F, OH, C₁₋₃alkyl, C₁₋₃    hydroxyalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃fluoroalkyl; wherein R is not    —OH or F if it is attached to a carbon atom which is adjacent to a    nitrogen atom:-   Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, indolyl,    indazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,    oxadiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, pyrazinyl,    oxazolyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, triazinyl,    azaindolyl, benzimidazolyl, bezoxazolyl, bezothiazolyl,    benzofuranyl, or benzothiophenyl.-   R² is a C₆₋₁₀ aryl, or a 5 to 10 membered heterocycle ring    containing 1 to 4 heteroatoms selected from N, O, and S, the    heterocycle optionally containing an oxo substitution, the aryl or    heterocycle are substituted with 0-3 R^(2a);-   R^(2a) is independently OH, ═O, CN, halo, C₁₋₄ alkyl, C₁₋₄    fluoroalkyl, C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, C₃₋₆ cycloalkyl, C₃₋₆    cycloalkoxy, C(═O)N(R^(4b)R^(4b)), C(═O)C₁₋₄ alkyl, SO₂R^(e), or a 4    to 6 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms selected    from O, S, and N, wherein the heterocycle is substituted with 0-3    R^(2b);-   R^(2b) is independently C₁₋₃ alkyl C₁₋₃ fluoralkyl, C₁₋₃    hydroxyalkyl, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl;-   R^(3a) is H, halo, OH, CN, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,    C₁₋₃fluoroalkyl, C₁₋₃alkoxy, C₃₋₆cycloalkyl, wherein if V is —O—,    —NR⁴—, —S—, —S(O)—, —SO₂—, or —C(═O)—, then R^(3a) is not halo;-   R^(3b) is H, OH, CN, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃fluoroalkyl,    C₁₋₃alkoxy, C₃₋₆cycloalkyl R⁴ is H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl,    C₂₋₃ hydroxyalkyl, CO₂R^(4a), C(═O)R^(4a), SO₂R^(4a),    C(═O)N(R^(4b)R^(4b)), or SO₂N(R^(4b)R^(4b));-   R^(4a) is C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered heterocycle having    1, 2, 3 or 4 heteroatoms selected from O, S, N, the aryl or    heterocycle being substituted with 0-3 R^(4c);-   R^(4b) is independently H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆    cycloalkyl, C₃₋₆-fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered    heterocycle having 1, 2 3 or 4 heteroatoms selected from O, S, N,-   alternatively, 2 R^(4b)'s, along with the atom to which they are    attached, join to form a 3-6 membered saturated ring containing and    additional 0-2 heteroatoms selected from O, S, or N;-   R^(4c) is independently H, F, Cl, or C₁₋₃ alkyl;-   R⁵ is independently H, F, OH, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, C₁₋₃    alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, or NR^(5b)R^(5b);-   R^(5b) is independently H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C(O)R^(a),    SO₂R^(a) or C(O)NR^(b)R^(b); alternatively, 2 R^(5b)'s, along with    the atom to which they are attached, join to form a 3-6 membered    saturated ring containing 0-2 heteroatoms selected from O, S, or N;-   R⁶ is independently H, C₁₋₃ alkyl, C₁₋₃ deuteroalkyl, C₁₋₃    fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl, C₁₋₃    hydroxylalkyl, C₁₋₃ hydroxydeuteroalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃    fluoroalkoxyalkyl;-   alternatively, 2 R⁶s attached to the same atom can form a 3-6    membered saturated ring containing 0-2 heteroatoms selected from O,    S, or N;-   R^(a) is H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered heterocycle having    1, 2 3 or 4 heteroatoms selected from O, S, N;-   R^(b) is H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered heterocycle having    1, 2 3 or 4 heteroatoms selected from O, S, N;-   each R^(d) is independently H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃    alkoxy, C₁₋₃ fluoroalkoxy, C₂₋₃ hydroxyalkyl, halo, OH, ═O, CN OCF₃,    OCHF₂, CHF₂ and CF₃; each R^(e) is independently H, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₃₋₆ cycloalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ alkoxyalkyl,    C₆₋₁₀ aryl, or a 5 to 10 membered heteroaryl having 1, 2, 3, or 4    heteroatoms selected from O, S, and N; and-   n is 0, 1, or 2.

In another aspect of the present invention provides at least onecompound of Formula (I):

or stereoisomer, tautomer, salt, pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein:

-   R¹ is:

-   each W is independently NR^(1b) or O;-   Z is a bond or CHR^(1d);-   X is N or CR^(1a), wherein X is N at only 0, 1, or 2 positions;-   each R^(1a) is independently H, F, Cl, —OH, —CN, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy, or C₁₋₃ fluoroalkoxy;-   each R^(1b) is independently H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, or    C₃₋₆ cycloalkyl;-   R^(1c) is H, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl;-   R^(1d) is H, C₁₋₃ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆ cycloalkyl;-   V is —O—, —NR⁴—, —CR⁵R⁵—, —S—, —S(O)—, —SO₂—, or —C(═O)—; wherein if    V is —O—, —S—, —S(O)—, —SO₂—, or —C(═O)—, then Y is not —SO₂, and    wherein if V is —O—, —S—, or NR⁴, then Y is not C(R⁶)₂;-   Y is —C(R⁶)₂—, —C(R⁶)₂—C(R⁶)₂—, —C(═O)—, —C(═O)—C(R⁶)₂—,    —C(R⁶)₂—C(═O)—, or —SO₂—;-   L¹ is —C(R)₂—, —C(═O)—, —C(R)₂—CH₂—, —CH₂—C(R)₂—, or —C(R)₂—C(R)₂;    wherein R is independently hydrogen, F, OH, C₁₋₃alkyl, C₁₋₃    hydroxyalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃fluoroalkyl; wherein R is not    —OH or F if it is attached to a carbon atom which is adjacent to a    nitrogen atom:-   Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, indolyl,    indazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,    oxadiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, pyrazinyl,    oxazolyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, triazinyl,    azaindolyl, benzimidazolyl, bezoxazolyl, bezothiazolyl,    benzofuranyl, or benzothiophenyl.-   R² is a C₆₋₁₀ aryl, or a 5 to 10 membered heterocycle ring    containing 1 to 4 heteroatoms selected from N, O, and S, the    heterocycle optionally containing an oxo substitution, the aryl or    heterocycle are substituted with 0-3 R^(2a);-   R^(2a) is independently OH, ═O, CN, halo, C₁₋₄alkyl, C₁₋₄    fluoroalkyl, C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, C₃₋₆ cycloalkyl, C₃₋₆    cycloalkoxy, C(═O)N(R^(4b)R^(4b)), C(═O)C₁₋₄ alkyl, SO₂R^(e), or a 4    to 6 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms selected    from O, S, and N, wherein the heterocycle is substituted with 0-3    R^(2b);-   R^(2b) is independently C₁₋₃ alkyl C₁₋₃ fluoralkyl, C₁₋₃    hydroxyalkyl, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl;-   R^(3a) is H, halo, OH, CN, C₁₋₃alkyl, C₁₋₃hydroxyalkyl,    C₁₋₃fluoroalkyl, C₁₋₃alkoxy, C₃₋₆cycloalkyl, wherein if V is —O—,    —NR⁴—, —S—, —S(O)—, —SO₂—, or —C(═O)—, then R^(3a) is not halo;-   R^(3b) is H, OH, CN, C₁₋₃alkyl, C₁₋₃hydroxyalkyl, C₁₋₃fluoroalkyl,    C₁₋₃alkoxy, C₃₋₆cycloalkyl-   R⁴ is H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₂₋₃ hydroxyalkyl, CO₂R^(4a),    C(═O)R^(4a), SO₂R^(4a), C(═O)N(R^(4b)R^(4b)), or SO₂N(R^(4b)R^(4b));-   R^(4a) is C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered heterocycle having    1, 2, 3 or 4 heteroatoms selected from O, S, N, the aryl or    heterocycle being substituted with 0-3 R^(4c);-   R^(4b) is independently H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆    cycloalkyl, C₃₋₆-fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered    heterocycle having 1, 2 3 or 4 heteroatoms selected from O, S, N,-   alternatively, 2 R^(4b)'s, along with the atom to which they are    attached, join to form a 3-6 membered saturated ring containing and    additional 0-2 heteroatoms selected from O, S, or N;-   R^(4c) is independently H, F, Cl, or C₁₋₃ alkyl;-   R⁵ is independently H, F, OH, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, C₁₋₃    alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, or NR^(5b)R^(5b);-   R^(5b) is independently H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, C(O)R^(a),    SO₂R^(a) or C(O)NR^(b)R^(b); alternatively, 2 R^(5b)'s, along with    the atom to which they are attached, join to form a 3-6 membered    saturated ring containing 0-2 heteroatoms selected from O, S, or N;-   R⁶ is independently H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆    cycloalkyl, C₃₋₆ fluorocycloalkyl, C₁₋₃ hydroxyl alkyl, C₁₋₃    alkoxyalkyl, or C₁₋₃ fluoroalkoxyalkyl; alternatively, 2 R⁶s    attached to the same atom can form a 3-6 membered saturated ring    containing 0-2 heteroatoms selected from O, S, or N;-   R^(a) is H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered heterocycle having    1, 2 3 or 4 heteroatoms selected from O, S, N;-   R^(b) is H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆    fluorocycloalkyl, C₆₋₁₀ aryl or a 4-10 membered heterocycle having    1, 2 3 or 4 heteroatoms selected from O, S, N;-   each R^(d) is independently H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃    alkoxy, C₁₋₃ fluoroalkoxy, C₂₋₃ hydroxyalkyl, halo, OH, ═O, CN OCF₃,    OCHF₂, CHF₂ and CF₃; each R^(e) is independently H, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₃₋₆ cycloalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ alkoxyalkyl,    C₆₋₁₀ aryl, or a 5 to 10 membered heteroaryl having 1, 2, 3, or 4    heteroatoms selected from O, S, and N; and-   n is 0, 1, or 2.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

R¹ is:

-   each R^(1a) is independently selected from F, Cl, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, and C₃₋₆ cycloalkyl;-   R^(1c) is H, deuterium, C₁₋₂ alkyl, or C₃₋₆ cycloalkyl;-   n is zero, 1, or 2.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-onyl,    pyrazolo[4,3-b]pyridinyl, pyridin-2-onyl, pyrazolyl,    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl,    pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiazolyl, thiophenyl,    1,2,3-triazolyl, benzo[d][1,2,3]triazolyl,    [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[d]imidazolyl, imidazolyl,    pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl,    pyrazolo[4,3-c]pyridinyl, pyrrolyl, pyrrolo[2,3-b]pyridinyl,    pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,    pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, tetrazolyl,    1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridazinyl,    pyrimidinyl, or benzo[d]oxazol-2-onyl, triazolyl, oxadiazolyl,    pyrrolopyridinyl, each being substituted with 0-3 R^(2a).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is pyridinyl, pyrimidinyl, pyrrazolyl, thiazolyl, imidazolyl,    triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl,    pyrazinyl, oxazolyl, or pyridazinyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   V is —O—, —NR⁴—, —CR⁵R⁵—, or —C(═O)—;-   wherein if V is —O—, or NR⁴, then Y is not C(R⁶)₂;-   Y is —C(R⁶)₂—, —C(R⁶)₂—C(R⁶)₂—, —C(═O)—, —C(═O)—C(R⁶)₂—, or    —C(R⁶)₂—C(═O)—;-   L¹ is —C(R)₂—, —C(═O)—, or —CH₂—C(R)₂—; wherein R is independently    from hydrogen, F, OH, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃    alkoxyalkyl, or C₁₋₃fluoroalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl, pyridinyl, indolyl, indazolyl,    benzo[d]oxazol-2(3H)-onyl, pyrazolo[4,3-b]pyridinyl,    pyridin-2(1H)-onyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazolyl,    triazolyl, oxadiazolyl, thiadiazolyl,    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl,    pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiophenyl,    [1,2,4]triazolo[4,3-b]pyridazinyl, pyrazolo[1,5-a]pyrimidinyl, or    benzo[d]oxazol-2(3H)-only, each being substituted with 0-3 R^(2a);    and-   R^(2a) is OH, ═O, CN, halo, SO₂C₁₋₄ alkyl, oxazolidin-2-one    substituted with 0-1 R^(2b);-   R^(2b) is C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, or C₁₋₃    fluoroalkoxy.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R¹ is

-   R^(1a) is H or —CH₃.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is pyridinyl, triazolyl, thiazolyl, oxadiazolyl, imidazolyl,    or pyrrazolyl; and-   R² is phenyl, pyridinyl, pyrimidinyl, benzo[d]oxazol-2(3H)-onyl,    imidazolyl, pyrrazolyl, triazolyl, or oxadiazolyl, each being    substituted with 0-3 R^(2a).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   V is —O—, —NR⁴—, or —CR⁵R⁵—;-   Y is —C(R⁶)₂—C(R⁶)₂— or —C(R⁶)₂—;-   L¹ is —C(R)₂—; wherein R is independently from hydrogen, F, OH,    C₁₋₃alkyl, C₁₋₃ hyroxyalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃fluoroalkyl;    and-   R⁶ is independently H, C₁₋₃-alkyl, C₁₋₃-fluoroalkyl, or    C₃₋₆-cycloalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: R¹ is:

-   one W is NR^(1b) and the other W is O;-   each R^(1a) is independently selected from F, Cl, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, and C₃₋₆ cycloalkyl;-   R^(1b) is H, C₁₋₃ alkyl, or C₁₋₃ fluoroalkyl;-   R^(1c) is H, C₁₋₂ alkyl, or C₃₋₆ cycloalkyl;-   n is zero, 1, or 2.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-onyl,    pyrazolo[4,3-b]pyridinyl, pyridin-2-onyl, 1H-pyrazolyl,    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl,    pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiazolyl, thiophenyl,    1,2,3-triazolyl, benzo[d][1,2,3]triazolyl,    [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[d]imidazolyl, imidazolyl,    pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl,    pyrazolo[4,3-c]pyridinyl, pyrrolyl, pyrrolo[2,3-b]pyridinyl,    pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,    pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, tetrazolyl,    1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridazinyl,    pyrimidinyl, or benzo[d]oxazol-2-onyl, each being substituted with    0-3 R^(2a).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, indolyl,    indazolyl, thiazolyl, imidizolyl, pyridinonyl, 1,2-dihydro-3H    pyrazol-3-onyl, 1H-1,2,3-triazolyl, pyrazinyl or pyridazinyl, or    oxazolyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, indolyl,    indazolyl, thiazolyl, imidizolyl, pyridinonyl, 1,2-dihydro-3H    pyrazol-3-onyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyrazinyl or    pyridazinyl, or oxazolyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, thiazolyl,    imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,    isoxazolyl, isothiazolyl, pyrrolyl, pyrazinyl, oxazolyl,    pyridazinyl, pyrrolidinyl, oxazolonyl, oxazolidinonyl,    pyrazolinonyl, imidazolidinyl, imidazolonyl, pyrrolidinonyl,    pyrimidinonyl, pyridazinonyl, or pyridinonyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is pyrazolyl, triazolyl, oxadiazolyl, isoxazolyl, imidzolyl,    or imidazolonyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   V is —O—, —NR⁴—, —CR⁵R⁵—, or —C(═O)—;-   wherein if V is —O—, or NR⁴, then Y is not C(R⁶)₂;-   Y is —C(R⁶)₂—, —C(R⁶)₂—C(R⁶)₂—, —C(═O)—, —C(═O)—C(R⁶)₂—, or    —C(R⁶)₂—C(═O)—;-   L¹ is —C(R)₂—, —C(═O)—, or —CH₂—C(R)₂—; wherein R is independently    from hydrogen, F, OH, C₁₋₃alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃    alkoxyalkyl, or C₁₋₃fluoroalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl, pyridinyl, indolyl, indazolyl,    benzo[d]oxazol-2(3H)-onyl, 1H-pyrazolo[4,3-b]pyridinyl,    pyridin-2(1H)-onyl, 1H-pyrazolyl, [1,2,4]triazolo[1,5-a]pyridinyl,    imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl,    thiophenyl, [1,2,4]triazolo[4,3-b]pyridazinyl,    pyrazolo[1,5-a]pyrimidinyl, or benzo[d]oxazol-2(3H)-only, each being    substituted with 0-3 R^(2a); and-   R^(2a) is OH, ═O, CN, halo, SO₂C₁₋₄ alkyl, oxazolidin-2-one    substituted with 0-1 R^(2b);-   R^(2b) is C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, or C₁₋₃    fluoroalkoxy.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl, pyridinyl, indolyl, indazolyl,    benzo[d]oxazol-2(3H)-onyl, 1H-pyrazolo[4,3-b]pyridinyl,    pyridin-2(1H)-onyl, 1H-pyrazolyl, [1,2,4]triazolo[1,5-a]pyridinyl,    imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl,    thiophenyl, [1,2,4]triazolo[4,3-b]pyridazinyl,    pyrazolo[1,5-a]pyrimidinyl, or benzo[d]oxazol-2(3H)-only, each being    substituted with 0-3 R^(2a); and-   R^(2a) is OH, ═O, CN, halo, C₁₋₄ alkyl, SO₂C₁₋₄ alkyl,    oxazolidin-2-one substituted with 0-1 R^(2b);-   R^(2b) is C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, or C₁₋₃    fluoroalkoxy.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R¹ is

and

-   R^(1a) is H or —CH₃.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is phenyl, pyridinyl, pyrimidinyl, indolyl, or pyrrazolyl,    indazolyl; and-   R² is phenyl, indolyl, pyridinyl, benzo[d]oxazol-2(3H)-onyl,    pyridin-2(1H)-onyl, or indazolyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl, pyridinyl, indolyl, indazolyl,    benzo[d]oxazol-2(3H)-onyl, pyrazolo[4,3-b]pyridinyl,    pyridin-2(1H)-onyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazolyl,    triazolyl, oxadiazolyl, thiadiazolyl,    [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl,    pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiophenyl,    [1,2,4]triazolo[4,3-b]pyridazinyl, pyrazolo[1,5-a]pyrimidinyl, or    benzo[d]oxazol-2(3H)-only, each being substituted with 0-3 R^(2a);    and-   R^(2a) is OH, ═O, CN, halo, SO₂C₁₋₄ alkyl, oxazolidin-2-one    substituted with 0-1 R^(2b);-   R^(2b) is C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, or C₁₋₃    fluoroalkoxy.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Y is —O—, —NR⁴—, or —CR⁵R⁵—;-   Y is —C(R⁶)₂—C(R⁶)₂—, —C(═O)—, —C(═O)—C(R⁶)₂— or —C(R⁶)₂—C(═O)—;-   L¹ is —C(R)₂—, —C(═O)—, or —CH₂—CH(R)—; wherein R is independently    from hydrogen, F, OH, C₁₋₃alkyl, C₁₋₃ hyroxyalkyl, C₁₋₃ alkoxyalkyl,    or C₁₋₃fluoroalkyl;-   R⁶ is independently H, C₁₋₃-alkyl, C₁₋₃-fluoroalkyl, or    C₃₋₆-cycloalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   V is —O—, —NR⁴—, or —CR⁵R⁵—;-   Y is —C(R⁶)₂—C(R⁶)₂—, or —C(R⁶)₂—;-   L¹ is —C(R)₂—; wherein R is independently from hydrogen, F, OH,    C₁₋₃alkyl, C₁₋₃ hyroxyalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃fluoroalkyl;    and-   R⁶ is independently H, C₁₋₃-alkyl, C₁₋₃-fluoroalkyl, or    C₃₋₆-cycloalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: R⁶ is independently H or C₁₋₃ alkyl; or R⁶ is independently Hor methyl; or R⁶ is methyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R^(2a) is OH, ═O, CN, halo, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₁₋₄    alkoxy, or C₁₋₄ fluoroalkoxy. Alternatively, R^(2a) is OH, ═O, CN,    halo, SO₂C₁₋₄ alkyl, oxazolidin-2-one substituted with 0-1 R^(2b);-   R^(2b) is C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, or C₁₋₃    fluoroalkoxy.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R⁴ is H, C₁₋₃-alkyl, CO₂R^(4a), C(═O)R^(4a), SO₂R^(4a),    C(═O)N(R^(4b)R^(4b)), SO₂N(R^(4b)R^(4b));-   R^(4a) is C₁₋₃-alkyl, C₁₋₃-fluoroalkyl, C₃₋₆-cycloalkyl;-   R^(4b) is independently H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,-   R⁵ is independently H, F, OH, C₁₋₃-alkoxy, C₁₋₃-alkyl,    C₃₋₆-cycloalkyl, NR^(5b)R^(5b);-   R^(5b) is independently H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C(O)R^(a),    SO₂R^(a) or C(O)NR^(b)R^(b).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R⁴ is H, C₁₋₃-alkyl, CO₂R^(4a), C(═O)R^(4a), SO₂R^(4a),    C(═O)N(R^(4b)R^(4b)), SO₂N(R^(4b)R^(4b));-   R^(4a) is C₁₋₃-alkyl, C₁₋₃-fluoroalkyl, C₃₋₆-cycloalkyl;-   R^(4b) is independently H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,-   R⁵ is independently H, F, OH, C₁₋₃-alkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the compound of Formula (I) is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R¹ is

and R^(1a) is H or —CH₃; or

-   R¹ is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R¹ is

and R^(1a) is H or —CH₃; and R^(1c) is independently H or deuterium; or

-   R¹ is

R^(1c) is independently H or deuterium.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R^(3a) and R^(3b) are H.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R¹ is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R¹ is

-   R^(1a) is H or —CH₃; R_(1b) is H or —CH₃; U is a bond, —CH₂—,    —CH₂CH₂—, —CH(CH₂OH)—, or —CH(OH)CH₂—.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: R^(1a) is H, F, C₁₋₃ alkyl, or CF₃; or R^(1a) is H.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: each R^(1b) is independently H, or C₁₋₃ alkyl; or each R^(1b)is H.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Ring B is

any of which are substituted with 0-1 R^(d).

In a ninth aspect of the invention, there are disclosed compounds ofFormula (I), or compounds of Formula (I) as described by any of theother embodiments or aspects, salts, enantiomers, diastereomers,tautomers, pharmaceutically-acceptable salts, hydrates, or solvatesthereof, wherein:

-   Ring B is phenyl, pyridinyl, pyrimidinyl, indolyl, pyrrazolyl, or    indazolyl; and-   R² is phenyl, indolyl, pyridinyl, benzo[d]oxazol-2(3H)-onyl,    pyridin-2(1H)-onyl, or indazolyl.

In a ninth aspect of the invention, there are disclosed compounds ofFormula (I), or compounds of Formula (I) as described by any of theother embodiments or aspects, salts, enantiomers, diastereomers,tautomers, pharmaceutically-acceptable salts, hydrates, or solvatesthereof, wherein:

-   Ring B is phenyl, pyridinyl, pyrimidinyl, indolyl, pyrrazolyl,    triazolyl or indazolyl; and-   R² is phenyl, indolyl, pyridinyl, benzo[d]oxazol-2(3H)-onyl,    pyridin-2(1H)-onyl, or indazolyl.

In another aspect of the invention, there are disclosed compounds ofFormula (I), or compounds of Formula (I) as described by any of theother embodiments or aspects, salts, enantiomers, diastereomers,tautomers, pharmaceutically-acceptable salts, hydrates, or solvatesthereof, wherein:

-   Ring B is phenyl, pyridinyl, pyrimidinyl, imidazolyl, oxadiazolyl,    pyrrazolyl, or triazolyl.

In another aspect of the invention, there are disclosed compounds ofFormula (I), or compounds of Formula (I) as described by any of theother embodiments or aspects, salts, enantiomers, diastereomers,tautomers, pharmaceutically-acceptable salts, hydrates, or solvatesthereof, wherein:

-   R² is phenyl, imidazolyl, pyridinyl, benzo[d]oxazol-2(3H)-onyl,    pyridin-2(1H)-onyl, pyrazinyl, pyrrazolyl, pyrrazolopyrimidinyl,    pyrimidinyl, thiazolyl, thiophenyl, or triazolyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: R^(2a) is CN, halo, or C₁₋₄alkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   -   R^(2a) is OH, ═O, CN, halo, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₁₋₄        alkoxy, C₁₋₄ fluoroalkoxy, SO₂R^(e), or oxazolidin-2-one        substituted with 0-1 R^(2b).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R^(2a) is independently OH, ═O, CN, halo, C₁₋₄ alkyl, C₁₋₄    deuteroalkyl, C₁₋₄ fluoroalkyl, C₁₋₄ alkoxy, C₁₋₄ deuteroalkoxy,    C₁₋₄ fluoroalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy,    C(═O)N(R^(4b)R^(4b)), C(═O)CM alkyl, SO₂R^(e), NR^(4b)SO₂R^(4b), or    a 4 to 6 membered heterocycle having 1, 2, 3, or 4 heteroatoms    selected from O, S, and N, wherein the heterocycle optionally    containing an oxo substitution and is substituted with 0-3 R^(2b);-   alternatively, two R^(2a) on adjacent atoms join to form —O—CH₂—O—,    or —O—CF₂—O—;

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   L¹ is —CH₂—, —C(═O)—, or —CH₂—CH(R)—; wherein R is independently    from hydrogen, F, OH, C₁₋₃ alkyl, C₁₋₃ hyroxyalkyl, C₁₋₃    alkoxyalkyl, or C₁₋₃fluoroalkyl; or-   L¹ is —CH₂—, —C(═O)—, or —CH₂—CH(R)—; wherein R is independently    from hydrogen, or OH; or-   L¹ is —CH₂—CH₂—, —CH₂—CH₂—.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the compound of Formula (I) is:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the compound of Formula (I) is:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the compound of formula (I) is:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the compound of formula (I) is:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl, pyridinyl, indolyl, indazolyl,    benzo[d]oxazol-2(3H)-onyl, 1H-pyrazolo[4,3-b]pyridinyl,    pyridin-2(1H)-onyl, 1H-pyrazolyl, [1,2,4]triazolo[1,5-a]pyridinyl,    imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl,    thiazolyl, thiophenyl, 1H-1,2,3-triazolyl,    1H-benzo[d][1,2,3]triazolyl, [1,2,4]triazolo[4,3-b]pyridazinyl,    1H-benzo[d]imidazolyl, 1H-imidazolyl, 1H-pyrazolo[3,4-b]pyridinyl,    1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl,    1H-pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl,    1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl,    pyrazolo[1,5-a]pyrimidinyl, 1H-tetrazolyl, 4H-1,2,4-triazolyl,    isothiazolyl, isoxazolyl, oxazolyl, pyridazinyl, pyrimidinyl, or    benzo[d]oxazol-2(3H)-only, each being substituted with 0-3 R^(2a).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is

each being substituted with 0-3 R^(2a) (as valance allows).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl,

each being substituted with 0-3 R^(2a) (as valance allows).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl,

each being substituted with 0-3 R^(2a) (as valence allows).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R² is phenyl,

each being substituted with 0-2 R^(2a) (as valance allows).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: the compounds are selected from the Examples.

In another aspect, there is disclosed a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and any one or morecompounds of Formula (I), or compounds of Formula (I) as described byany of the other embodiments or aspects or examples, or apharmaceutically acceptable salt thereof.

In another aspect, there is disclosed a method for the treatment of oneor more diseases or disorders which can be modulated by inhibition ofROMK, comprising administering to a patient in need of such treatment orprophylaxis a therapeutically effective amount of at least one of thecompounds of Formula (I), or compounds of Formula (I) as described byany of the other embodiments or aspects or examples, wherein the diseaseor disorder is treated by promotion of diuresis or natriuresis.

In another aspect, there is disclosed a method for the treatment orprophylaxis of one or more diseases or disorders which can be modulatedby ROMK inhibition, wherein the compound of any of the embodiments isadministered in combination with at least one other type of therapeuticagent.

In another aspect, there is disclosed a method for the treatment orprophylaxis of multiple diseases or disorders, comprising administeringto a patient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, wherein the disease or disorder is treated by the promotion ofdiuresis or natriuresis, or for ROMK associated disorders.

In another aspect, there is disclosed a method for the treatment orprophylaxis of diseases or disorders, wherein the compound of any of theembodiments is administered in combination with at least one other typeof therapeutic agent. In another aspect, the present invention providesa compound selected from the exemplified examples or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds within the scope of the examples.

In another aspect, the present invention provides treatment ofhypertension or heart failure for patients in need of diuresis ornatriuresis.

In another aspect, the present invention provides for the treatment ofhypertension.

In another aspect, the present invention provides for the treatment ofhypertension, idiopathic hypertension, regractory hypertension, and/orpulmonary hypertension.

In another aspect, the present invention provides for the treatment ofheart failure.

In another aspect, the present invention provides for the treatment ofedema, cardiac insufficiency, systolic heart failure, diastolic heartfailure, diabetic heart failure, and/or acute-decompensated heartfailure.

The present invention may be embodied in other specific forms withoutparting from the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also understoodthat each individual element of the embodiments is its own independentembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phrase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I); and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds. Where a substituent definition represents more than onesubstituent, each substituent is independently selected from the othersubstituent(s).

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “cyano” refers to the group —CN.

The term “amino” refers to the group —NH₂.

The term “oxo” refers to the group ═O.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms, and is intended to include C₁, C₂, C₃, and C₄ alkylgroups. Examples of alkyl groups include, but are not limited to, methyl(Me), ethyl (Et), propyl (e.g, n-propyl and i-propyl), butyl (e.g.,n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl,isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₆ alkyl” denotes straight and branched chain alkyl groups with oneto six carbon atoms.

The term “haloalkyl” as used herein is intended to include both branchedand straight-chain saturated aliphatic hydrocarbon groups substitutedwith one or more halogen atoms. For example, “C₁₋₄ haloalkyl” isintended to include C₁, C₂, C₃, and C₄ alkyl groups substituted with oneor more halogen atoms. Representative examples of haloalkyl groupsinclude, but are not limited to, —CF₃, —CCl₃, —CFCl₃, and —CH₂CF₃.

The term “fluoroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more fluorine atoms. For example, “C₁₋₄fluoroalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more fluorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CF₃ and —CH₂CF₃.

The term “hydroxyalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups. Forexample, “hydroxyalkyl” includes —CH₂OH, —CH₂CH₂OH, and C₁₋₄hydroxyalkyl.

The term “cycloalkyl,” as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C₃₋₆ cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom, for example, methoxygroup (—OCH₃). For example, “C₁₋₃ alkoxy” denotes alkoxy groups with oneto three carbon atoms. The terms “haloalkoxy” and “—O(haloalkyl)”represent a haloalkyl group as defined above attached through an oxygenlinkage (—O—). For example, “C₁₋₄ haloalkoxy” is intended to include C₁,C₂, C₃, and C₄ haloalkoxy groups.

The terms “fluoroalkoxy” and “—O(fluoroalkyl)” represent a fluoroalkylgroup as defined above attached through an oxygen linkage (—O—). Forexample, “C₁₋₄ fluoroalkoxy” is intended to include C₁, C₂, C₃, and C₄fluoroalkoxy groups.

The term “aryl” as used herein, refers to a group of atoms derived froma molecule containing aromatic ring(s) by removing one hydrogen that isbonded to the aromatic ring(s), containing 4 to 10, or 6 to 10 carbonatoms. Aryl groups that have two or more rings must include onlyaromatic rings. Representative examples of aryl groups include, but arenot limited to, phenyl and naphthyl. The aryl ring may be unsubstitutedor may contain one or more substituents as valence allows.

The term “benzyl,” as used herein, refers to a methyl group in which oneof the hydrogen atoms is replaced by a phenyl group. The phenyl ring maybe unsubstituted or may contain one or more substituents as valenceallows.

The term “heteroatom” refers to oxygen (O), sulfur (S), and nitrogen(N).

The terms “heterocyclyl” or “heterocycle” as used herein, refers tosubstituted and unsubstituted saturated, partially saturated, andaromatic 3-to 7-membered monocyclic groups, 7-to 11-membered bicyclicgroups, and 10-to 15-membered tricyclic groups, in which at least one ofthe rings has at least one heteroatom (O, S or N), said heteroatomcontaining ring having 1, 2, 3, or 4 heteroatoms selected from O, S, andN. Each ring of such a group containing a heteroatom can contain one ortwo oxygen or sulfur atoms and/or from one to four nitrogen atomsprovided that the total number of heteroatoms in each ring is four orless, and further provided that the ring contains at least one carbonatom. The nitrogen and sulfur atoms may optionally be oxidized and thenitrogen atoms may optionally be quaternized. The fused rings completingthe bicyclic and tricyclic groups may contain other heteroatoms or onlycarbon atoms; and may be saturated, partially saturated, or aromatic.The heterocyclo group may be attached at any available nitrogen orcarbon atom in the heterocyclo group. The term “heterocyclyl” includes“heteroaryl” groups. As valence allows, if said further ring iscycloalkyl or heterocyclo it is additionally optionally substituted with═O (oxo).

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups,and 11- to 14-membered tricyclic groups that have at least oneheteroatom (O, S or N) in at least one of the rings, saidheteroatom-containing ring preferably having 1, 2, or 3 heteroatomsindependently selected from O, S, and/or N. Each ring of the heteroarylgroup containing a heteroatom can contain one or two oxygen or sulfuratoms and/or from one to four nitrogen atoms provided that the totalnumber of heteroatoms in each ring is four or less and each ring has atleast one carbon atom. The fused rings completing the bicyclic group arearomatic and may contain other heteroatoms or only carbon atoms. Thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenatoms may optionally be quaternized. Bicyclic and tricyclic heteroarylgroups must include only aromatic rings. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring. Theheteroaryl ring system may be unsubstituted or may contain one or moresubstituents.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can be provided as amorphous solids orcrystalline solids. Lyophilization can be employed to provide thecompounds of Formula (I) as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formula (I) with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

Various forms of prodrugs are well known in the art and are describedin:

-   a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al.,    Ch 31, (Academic Press, 1996);-   b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson    and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic    Publishers, 1991); and-   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and    Joachim M. Mayer, (Wiley-VCH, 2003).

In addition, compounds of Formula (I), subsequent to their preparation,can be isolated and purified to obtain a composition containing anamount by weight equal to or greater than 99% of a compound of Formula(I) (“substantially pure”), which is then used or formulated asdescribed herein. Such “substantially pure” compounds of Formula (I) arealso contemplated herein as part of the present invention.

Compounds of the formula I and/or the Examples herein may in some casesform salts which are also within the scope of this invention. Referenceto a compound of the formula I and/or Examples herein is understood toinclude reference to salts thereof, unless otherwise indicated. The term“salt(s)”, as employed herein, denotes acidic and/or basic salts formedwith inorganic and/or organic acids and bases. Zwitterions (internal orinner salts) are included within the term “salt(s)” as used herein (andmay be formed, for example, where the R substituents comprise an acidmoiety such as a carboxyl group). Also included herein are quaternaryammonium salts such as alkylammonium salts. Pharmaceutically acceptable(i.e., non-toxic, physiologically acceptable) salts are preferred,although other salts are useful, for example, in isolation orpurification steps which may be employed during preparation. Salts ofthe compounds of the formula I may be formed, for example, by reacting acompound I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization. As used herein, “pharmaceuticallyacceptable salts” refer to derivatives of the disclosed compoundswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic groups such asamines; and alkali or organic salts of acidic groups such as carboxylicacids. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, and nitric; and the salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

“Base addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free acids, which are notbiologically or otherwise undesirable. These salts are prepared fromaddition of an inorganic base or an organic base to the free acid. Saltsderived from inorganic bases include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese, aluminum salts and the like. In one aspect, inorganicsalts are the ammonium, sodium, potassium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. In anotheraspect, organic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds. Combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to act as aninhibitor to ROMK, or effective to treat or prevent cardiovasculardisease.

In another aspect, there is disclosed a method for the treatment orprophylaxis of one or more disease or disorder which can be modulated byROMK inhibition, comprising administering to a patient in need of suchtreatment or prophylaxis a therapeutically effective amount of at leastone of the compounds of Formula (I), or compounds of Formula (I) asdescribed by any of the other emodiments or aspects, wherein the diseaseor disorder is treated by the promotion of diuresis or natriuresis.

In another aspect, there is disclosed a method for the treatment of oneor more disease or disorder which can be treated by promotion ofdiuresis or natriuresis, wherein the cardiovascular diseases include,but are not limited to, hypertension, coronary heart disease, stroke,heart failure, systolic heart failure, diastolic heart failure, diabeticheart failure, acute-decompensated heart failure, post-operative volumeoverload, idiopathic edema, pulmonary hypertension, pulmonary arterialhypertension, refractory hypertension cardiac insufficiency, nephroticsyndrome and acute kidney insufficiency.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds, whether thoseisotopes occur in their natural abundancy, or are enriched to a levelgreater than its natural abundancy. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuterium(D) and tritium (T). Isotopes of carbon include ¹³C and ¹⁴C. Forexample, methyl (—CH₃) also includes deuterated methyl groups such as—CD₃, —CHD₂, or —CH₂D.

Compounds in accordance with Formula (I) can be administered by anymeans suitable for the condition to be treated, which can depend on theneed for site-specific treatment or quantity of Formula (I) compound tobe delivered.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising a compound of Formula (I) and one or morenon-toxic, pharmaceutically-acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) and,if desired, other active ingredients. The compounds of Formula (I) maybe administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly, and intrasternallyin dosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. For example, thepharmaceutical carrier may contain a mixture of mannitol or lactose andmicrocrystalline cellulose. The mixture may contain additionalcomponents such as a lubricating agent, e.g. magnesium stearate and adisintegrating agent such as crospovidone. The carrier mixture may befilled into a gelatin capsule or compressed as a tablet. Thepharmaceutical composition may be administered as an oral dosage form oran infusion, for example.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, liquid capsule, suspension, orliquid. The pharmaceutical composition is preferably made in the form ofa dosage unit containing a particular amount of the active ingredient.For example, the pharmaceutical composition may be provided as a tabletor capsule comprising an amount of active ingredient in the range offrom about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, andmore preferably from about 0.5 to 100 mg. A suitable daily dose for ahuman or other mammal may vary widely depending on the condition of thepatient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, bedelivered orally via any acceptable and suitable oral preparations.Exemplary oral preparations, include, but are not limited to, forexample, tablets, troches, lozenges, aqueous and oily suspensions,dispersible powders or granules, emulsions, hard and soft capsules,liquid capsules, syrups, and elixirs. Pharmaceutical compositionsintended for oral administration can be prepared according to anymethods known in the art for manufacturing pharmaceutical compositionsintended for oral administration. In order to provide pharmaceuticallypalatable preparations, a pharmaceutical composition in accordance withthe invention can contain at least one agent selected from sweeteningagents, flavoring agents, coloring agents, demulcents, antioxidants, andpreserving agents.

A tablet can, for example, be prepared by admixing at least one compoundof Formula (I) with at least one non-toxic pharmaceutically acceptableexcipient suitable for the manufacture of tablets. Exemplary excipientsinclude, but are not limited to, for example, inert diluents, such as,for example, calcium carbonate, sodium carbonate, lactose, calciumphosphate, and sodium phosphate; granulating and disintegrating agents,such as, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, and alginic acid; binding agents, such as,for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; andlubricating agents, such as, for example, magnesium stearate, stearicacid, and talc. Additionally, a tablet can either be uncoated, or coatedby known techniques to either mask the bad taste of an unpleasanttasting drug, or delay disintegration and absorption of the activeingredient in the gastrointestinal tract thereby sustaining the effectsof the active ingredient for a longer period. Exemplary water solubletaste masking materials, include, but are not limited to,hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplarytime delay materials, include, but are not limited to, ethyl celluloseand cellulose acetate butyrate.

Hard gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one inert solid diluent, suchas, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at leastone compound of Formula (I) with at least one water soluble carrier,such as, for example, polyethylene glycol; and at least one oil medium,such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at leastone compound of Formula (I) with at least one excipient suitable for themanufacture of an aqueous suspension. Exemplary excipients suitable forthe manufacture of an aqueous suspension, include, but are not limitedto, for example, suspending agents, such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth,and gum acacia; dispersing or wetting agents, such as, for example, anaturally-occurring phosphatide, e.g., lecithin; condensation productsof alkylene oxide with fatty acids, such as, for example,polyoxyethylene stearate; condensation products of ethylene oxide withlong chain aliphatic alcohols, such as, for exampleheptadecaethylene-oxycetanol; condensation products of ethylene oxidewith partial esters derived from fatty acids and hexitol, such as, forexample, polyoxyethylene sorbitol monooleate; and condensation productsof ethylene oxide with partial esters derived from fatty acids andhexitol anhydrides, such as, for example, polyethylene sorbitanmonooleate. An aqueous suspension can also contain at least onepreservative, such as, for example, ethyl and n-propylp-hydroxybenzoate; at least one coloring agent; at least one flavoringagent; and/or at least one sweetening agent, including but not limitedto, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at leastone compound of Formula (I) in either a vegetable oil, such as, forexample, arachis oil; olive oil; sesame oil; and coconut oil; or inmineral oil, such as, for example, liquid paraffin. An oily suspensioncan also contain at least one thickening agent, such as, for example,beeswax; hard paraffin; and cetyl alcohol. In order to provide apalatable oily suspension, at least one of the sweetening agents alreadydescribed hereinabove, and/or at least one flavoring agent can be addedto the oily suspension. An oily suspension can further contain at leastone preservative, including, but not limited to, for example, ananti-oxidant, such as, for example, butylated hydroxyanisol, andalpha-tocopherol.

Dispersible powders and granules can, for example, be prepared byadmixing at least one compound of Formula (I) with at least onedispersing and/or wetting agent; at least one suspending agent; and/orat least one preservative. Suitable dispersing agents, wetting agents,and suspending agents are as already described above. Exemplarypreservatives include, but are not limited to, for example,anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders andgranules can also contain at least one excipient, including, but notlimited to, for example, sweetening agents; flavoring agents; andcoloring agents.

An emulsion of at least one compound of Formula (I) thereof can, forexample, be prepared as an oil-in-water emulsion. The oily phase of theemulsions comprising compounds of Formula (I) may be constituted fromknown ingredients in a known manner. The oil phase can be provided by,but is not limited to, for example, a vegetable oil, such as, forexample, olive oil and arachis oil; a mineral oil, such as, for example,liquid paraffin; and mixtures thereof. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Suitableemulsifying agents include, but are not limited to, for example,naturally-occurring phosphatides, e.g., soy bean lecithin; esters orpartial esters derived from fatty acids and hexitol anhydrides, such as,for example, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, such as, for example, polyoxyethylenesorbitan monooleate. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. An emulsion can also contain a sweeteningagent, a flavoring agent, a preservative, and/or an antioxidant.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The compounds of Formula (I) can, for example, also be deliveredintravenously, subcutaneously, and/or intramuscularly via anypharmaceutically acceptable and suitable injectable form. Exemplaryinjectable forms include, but are not limited to, for example, sterileaqueous solutions comprising acceptable vehicles and solvents, such as,for example, water, Ringer's solution, and isotonic sodium chloridesolution; sterile oil-in-water microemulsions; and aqueous or oleaginoussuspensions.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e.propylene glycol) or micellar solubilization (i.e. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, beprepared by 1) dissolving at least one compound of Formula (I) in anoily phase, such as, for example, a mixture of soybean oil and lecithin;2) combining the Formula (I) containing oil phase with a water andglycerol mixture; and 3) processing the combination to form amicroemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordancewith methods already known in the art. For example, a sterile aqueoussolution or suspension can be prepared with a non-toxicparenterally-acceptable diluent or solvent, such as, for example,1,3-butane diol; and a sterile oleaginous suspension can be preparedwith a sterile non-toxic acceptable solvent or suspending medium, suchas, for example, sterile fixed oils, e.g., synthetic mono- ordiglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants usedin pharmaceutical dosage forms such as Tweens, polyethoxylated castoroil such as CREMOPHOR surfactant (BASF), or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions can be presented in a pack or dispenserdevice which can contain one or more unit dosage forms including thecompound of Formula (I). The pack can, for example, comprise metal orplastic foil, such as a blister pack. The pack or dispenser device canbe accompanied by instructions for administration.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals. The pharmaceutical compositions may be subjected toconventional pharmaceutical operations such as sterilization and/or maycontain conventional adjuvants, such as preservatives, stabilizers,wetting agents, emulsifiers, and buffers. Tablets and pills canadditionally be prepared with enteric coatings. Such compositions mayalso comprise adjuvants, such as wetting, sweetening, flavoring, andperfuming agents.

The amounts of compounds that are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex, the medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 to 100 mg/kg body weight, preferably between about0.0025 and about 50 mg/kg body weight and most preferably between about0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can beadministered in one to four doses per day. Other dosing schedulesinclude one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered orally, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

Pharmaceutical compositions of this invention comprise at least onecompound of Formula (I) and optionally an additional agent selected fromany pharmaceutically acceptable carrier, adjuvant, and vehicle.Alternate compositions of this invention comprise a compound of theFormula (I) described herein, or a prodrug thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

The pharmaceutical compositions may contain other therapeutic agents andmay be formulated, for example, by employing conventional solid orliquid vehicles or diluents, as well as pharmaceutical additives of atype appropriate to the mode of desired administration (e.g, excipients,binders, preservatives, stabilizers, and flavors) according totechniques such as those well known in the art of pharmaceuticalformulation.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a cardiovascular disorder, diuresis,and/or natriuresis. In another embodiment, the package insert statesthat the pharmaceutical composition can be used in combination (asdefined previously) with a second therapeutic agent to treatcardiovascular disorder, diuresis, and/or natriuresis. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g, for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g, paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, or other written sheet thatrecites information relating to the pharmaceutical composition locatedwithin the first container. The information recited will usually bedetermined by the regulatory agency governing the area in which thearticle of manufacture is to be sold (e.g, the United States Food andDrug Administration). Preferably, the package insert specificallyrecites the indications for which the pharmaceutical composition hasbeen approved. The package insert may be made of any material on which aperson can read information contained therein or thereon. Preferably,the package insert is a printable material (e.g., paper, plastic,cardboard, foil, adhesive-backed paper or plastic) on which the desiredinformation has been formed (e.g, printed or applied).

UTILITY

The compounds of the invention inhibit the activity of ROMK.Accordingly, compounds of Formula (I) have utility in treatingconditions associated with the inhibition of ROMK.

The compounds described herein are intended for the treatment and/orprophylaxis of any disorders that benefit from increased excretion ofwater and sodium from the body, or for any patient in need of diuresisor natriuresis. Specific disorders would include any form ofhypertension or heart failure (acute-decompensated and chronic,diastolic and systolic). For heart failure treatment, the compoundswould be used to treat acute-decompensated heart failure to reduce edemaand other symptoms and/or to overcome resistance to other classes ofdiuretics, or to shorten hospital stay. The compounds could also be usedin heart failure after discharge from hospital or during chronic therapyto treat symptoms and reduce recurrences of acute-decompensations andhospital admissions. Other disorders for which a diuretic or natriureticor both would have therapeutic or prophylactic benefit includepost-operative volume overload, any edematous states includingidiopathic edema, pulmonary hypertension including pulmonary arterialhypertension, cardiac insufficiency, nephrotic syndrome and acute kidneyinsufficiency.

The compounds in accordance with the present invention are beneficial inthe treatment and/or prevention of various human ailments. The compoundsin accordance with the present invention can be beneficial either as astand alone therapy or in combination with other therapies thattherapeutically could provide greater benefit. The ailments for whichthe compounds in the present invention could be of benefit includecardiovascular disease; and promotion of diuresis or natriuresis.

One embodiment provides a method for treating cardiovascular disease.Particular, cardiovascular diseases include, but are not limited to,hypertension, coronary heart disease, stroke, heart failure, systolicheart failure, diastolic heart failure, diabetic heart failure,acute-decompensated heart failure, post-operative volume overload,idiopathic edema, pulmonary hypertension, pulmonary arterialhypertension, cardiac insufficiency, nephrotic syndrome and acute kidneyinsufficiency. For example, a therapeutically effective amount fortreating a disorder may be administered in the method of the presentembodiment.

One embodiment provides a method for the promotion of diuresis ornatriuresis.

One or more additional pharmacologically active agents may beadministered in combination with the compounds described hereinincluding any other diuretic from any other diuretic class (thiazides,loops, potassium-sparing, osmotic, carbonic anhydrase inhibitors,mineralocorticoid receptor antagonists), acetylcholinesteraseinhibitors, angiotensin receptor blockers, neutral endopeptidaseinhibitors, dual angiotensin receptor antagonists and neutralendopeptidase inhibitors, aldosterone antagonists, natriuretic peptides,calcium channel blockers, relaxin or relaxin mimetics, inotropic agents,peripheral vasodilators, or mineralocorticoid receptor antagonists. Oneembodiment provides the compounds of Formula (I) for use in therapy. Inthe present embodiment, the use in therapy may include theadministration of a therapeutically-effective amount of a compound ofFormula (I).

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for the treatment ofcardiovascular disease. In the present embodiment, the use for themanufacture of a medicament may include the administration of atherapeutically-effective amount of a compound of Formula (I) for thetreatment of cardiovascular disease.

The present invention also provides the use of the compounds of Formula(I) for the manufacture of a medicament for promotion of diuresis ornatriuresis.

In one embodiment, the compounds of Formula (I) inhibit ROMK activitywith IC₅₀ values of less than 10 μM, for example, from 0.001 to lessthan 10 μM, as measured by the Thallium Flux assay. Preferably, thecompounds of Formula (I) inhibit ROMK activity with IC₅₀ values of lessthan 1 μM, for example, from 0.001 to less than 1 μM. Other compoundsinhibit ROMK activity with IC₅₀ values of 100 nM and less, for example,from 1 to 100 nM.

Examples of compounds of Formula (I) as specified in the “Examples”section below, have been tested in one or more of the assays describedbelow.

Methods of Preparation

The following are the definitions of symbols used.

-   -   Ar Aryl    -   ACN Acetonitrile    -   BF₃.OEt₂ Boron trifluoride etherate    -   CH₂Cl₂ Dichloromethane    -   CHCl₃ Chloroform    -   CDCl₃ Deuterated chloroform    -   CD₃OD Deuterated methanol    -   DCM Dichloromethane    -   DMAP 4-Dimethylaminopyridine    -   DMF N,N-dimethyl formamide    -   DMSO Dimethyl sulfoxide    -   DMSO-d₆ Deuterated dimethyl sulfoxide    -   Et Ethyl    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   HATU (O)-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium        hexafluorophosphate)    -   HCl Hydrochloric acid    -   HCOOH Formic acid    -   HCOONH₄ Ammonium formate    -   KI Potassium iodide    -   K₂CO₃ Potassium carbonate    -   KOAc Potassium acetate    -   K₃PO₄ Potassium phosphate    -   LiOH Lithium hydroxide    -   Me Methyl    -   MeOH Methanol    -   NaH Sodium hydride    -   NaHCO₃ Sodium bicarbonate    -   NaNO₂ Sodium nitrite    -   Na₂SO₄ Sodium sulfate    -   Na₂S₂O₃ Sodium thiosulfate    -   NH₃ Ammonia    -   NH₄OAc Ammonium acetate    -   Pd/C Palladium on carbon    -   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium (0)    -   Pd(dppf)₂Cl₂:CH₂Cl₂        [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium(II),        complex with dichloromethane    -   POCl₃ Phosphorus oxychloride    -   THF Tetrahydrofuran    -   TFA Trifluoroacetic acid    -   XANTPHOS 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene    -   IPA Isopropyl alcohol    -   DEA Diethylamine    -   STAB Sodium triacetoxyborohydride

Synthesis:

A particularly useful compendium of synthetic methods which may beapplicable to the preparation of compounds of the present invention maybe found in Larock, R. C., Comprehensive Organic Transformations, VCH,New York (1989). Preferred methods include, but are not limited to,those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituent's that arecompatible with the reaction conditions will be readily apparent to oneskilled in the art and alternate methods must then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,Wiley and Sons (1991)).

Intermediates of general formula D may be synthesized according toScheme 1.

Substituted epoxides (A) were converted to (B) by reaction withappropriate amine. B was subjected to alkylation, acylation or mitsunobuinversion reactions with appropriately substituted alkyl amines oralkyl/acylhalides to generate (C). Compound C was deprotected usingchoroethylchioroformate, TFA or hydrogenation in the presence of Pd/Cfollowed by cyclization to generate intermediate (D). Intermediate D(X═N) was also synthesized by an alternative route using appropriatelysubstituted aryl halides (E), were E was converted to (F) using Suzukicoupling of appropriately substituted halo pyrazines followed byreduction of F under hydrogen pressure in the presence of Palladium(II)acetate to generate intermediate (D).

Intermediates of general formula I may be synthesized according toScheme 2.

Appropriately substituted aryl halides (E) were subjected to the C—Hactivation reaction in presences of N-protected and appropriatelysubstituted piperidinone/pyrrolidinone to generate H. Compound H wassubjected to reduction and/or fluorination followed by N-deprotection togenerate intermediates of the general formula (I).

Compounds of general formula K, L, N and O may be synthesized accordingto Scheme 3.

Aldehydes J and M were synthesized according to literature proceduresand J and M were subjected to reductive amination with borane reagentslike sodium triacetoxyborohydride and appropriately substitutedintermediates (D or I) to generate compounds of the general formula K,L, N and O.

Compounds of general formula Q and R may be synthesized according toScheme 4.

Intermediates P and C was synthesized according to literatureprocedures. Intermediates P and C were subjected to deprotection, andreductive amination of deprotected amine with appropriately substitutedaldehydes (J or M) in presence of borane reagents like sodiumcyanoborohydride followed by cyclization generate compounds of thegeneral formula Q and R.

General Methods:

The following methods were used in the working Examples, except wherenoted otherwise.

Analytical HPLC and HPLC/MS methods employed in characterization ofexamples:

Reverse phase analytical HPLC/MS was performed on Shimadzu LC10ASsystems coupled with Waters ZMD Mass Spectrometers or Waters Aquitysystem coupled with a Waters Micromass ZQ Mass Spectrometer. Chiralanalytical LC was performed on a Berger Analytical SFC instrument.

Method A:

Ascentis Express CIS (2.1×50 mm) 2.7 micron; Solvent A: 95% water, 5%acetonitrile, 0.1% TEA; Solvent B: 95% acetonitrile, 5% water, 0.1% TEA;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then 1 minutehold at 100% B; Flow: 1.1 mL/min, UV 220 nm.

Method B:

Ascentis Express CIS (2.1×50 mm) 2.7 micron; Solvent A: 95% water, 5%acetonitrile with 10 mM ammonium acetate; Solvent B: 95% acetonitrile,5% water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient:0-100% B over 3 minutes, then 1 minute hold at 100% B; Flow: 1.1 mL/min,UV 220 nm.

Method C:

SunFire CIS (4.6×150 mm) 5.0 micron; Solvent A: 95% water, 5%acetonitrile, 0.05% TEA; Solvent B: 5% water, 95% acetonitrile, 0.05%TEA; Gradient: 50-100% B over 15 minutes, then 5 minute hold at 100% B;Flow: 1.1 mL/min, UV 220 nm.

Method D:

Kinetex, XB CIS (2.6 μm×75.3 mm); Solvent A: 10 mM NH₄CO₂H in 98% water,2% acetonitrile; Solvent B: 10 mM NH₄CO₂H in 2% water, 98% acetonitrile,Gradient: 20-100% B over 4 minutes, then 0.6 minute hold at 100% B;Flow: 1.1 mL/min, UV 220 nm.

Method E:

Sunfire C18 (4.6×150 mm) 3.5 micron; Solvent A: 95% water, 5%acetonitrile, 0.05% TEA; Solvent B: 5% water, 95% acetonitrile, 0.05%TEA; Gradient: 10-100% B over 25 minutes, then 5 minutes hold at 100% B;Flow: 1.1 mL/min, UV 254 nm.

Method F:

Sunfire C18 (4.6×150 mm) 3.5 micron; Solvent A: 95% water, 5%acetonitrile, 0.05% TEA; Solvent B: 5% water, 95% acetonitrile, 0.05%TEA; Gradient: 10-100% Solvent B over 18 minutes, then 5 minutes hold at100% B; Flow: 1.1 mL/min, UV 220 nm.

Method G:

XBridge Phenyl (4.6×150 mm) 3.5 micron; Solvent A: 95% water, 5%acetonitrile, 0.05% TFA; Solvent B: 5% water, 95% acetonitrile, 0.05%TFA; Gradient: 10-100% Solvent B over 18 minutes, then 5 minutes hold at100% B; Flow: 1.1 mL/min, UV 220 nm.

Method H:

ZORBAX SB C18 (4.6×50 mm) 5.0 micron; Solvent A: 10 mM NH₄CO₂H in 98%water, 2% acetonitrile; Solvent B: 10 mM NH₄CO₂H in 2% water, 98%acetonitrile, Gradient: 30-100% B over 4 minutes, then 0.6 minute holdat 100% B; Flow: 1.0 mL/min, UV 220 nm.

Method I:

Acquity BEH C18 (2.1×50 mm) 1.7 micron; Solvent A: 10 mM ammoniumacetate in 95% water, 5% acetonitrile; Solvent B: 10 mM ammonium acetatein 5% water, 95% acetonitrile, Gradient: 20-90% B over 1.1 minutes, then0.7 minute hold at 90% B; Flow: 0.5 mL/min, UV 220 nm.

Method J:

Kinetex XB-C18 (3×75 mm) 2.6 micron; Solvent A: 0.1% HCOOH in water;Solvent B: Acetonitrile, Gradient: 20-90% B over 1.1 minutes, then 0.7minute hold at 90% B; Flow: 0.5 mL/min, UV 220 nm.

Method K:

Kinetex C18 (2.1×50 mm) 2.6 micron; Solvent A: 5 mM ammonium acetate in95% water, 5% acetonitrile; Solvent B: 5 mM ammonium acetate in 5%water, 95% acetonitrile, Gradient: 20-90% B over 1.1 minutes, then 0.6minute hold at 90% B; Flow: 0.7 mL/min, UV 220 nm.

Method L:

Acquity BEH C18 (3×50 mm) 1.7 micron; Solvent A: 0.1% TFA in water,Solvent B: 0.1% TFA in ACN, Gradient: 20-90% B over 1.0 minutes, then0.6 minute hold at 90% B; Flow: 0.7 mL/min, UV 220 nm.

Method M:

Xbridge Phenyl (21.2×250 ID) 5 micron; Solvent A: 0.1% TFA in water,Solvent B: Acetonitrile, Gradient: 5-25% B over 1.0 minutes, then 0.6minute hold at 90% B Flow: 0.7 mL/min, UV 220 nm.

Method N:

ZORBAX SB C18 (4.6×50 mm) 5.0 micron; Solvent A: 0.1% TFA in 95% water,5% acetonitrile; Solvent B: 0.1% TFA in 5% water, 95% acetonitrile,Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min, UV 220 nm.

Method O:

Acquity UPLC BEH C18 (3×50 mm) 1.7 micron; Solvent A: 5 mM ammoniumacetate in 95% water, 5% acetonitrile; Solvent B: 5 mM ammonium acetatein 5% water, 95% acetonitrile, Gradient: 20-90% B over 1.1 minutes, then0.6 minute hold at 90% B; Flow: 0.7 mL/min, UV 220 nm.

Method P:

Kinetex EVO C18 (4.6×100 mm) 2.6 micron; Solvent A: 95% water, 5%acetonitrile, 0.05% TEA; Solvent B: 5% water, 95% acetonitrile, 0.05%TEA; Gradient: 20-100% B over 11 minutes, then 1.5 minute hold at 100%B; Flow: 1.0 mL/min, UV 300 nm.

Method Q:

Kinetex Biphenyl (4.6×11 mm) 2.6 micron; Solvent A: 0.05% TFA in water;Solvent B: Acetonitrile, Gradient: 20-100% B over 11 minutes, then 1.5minute hold at 100% B; Flow: 1.0 mL/min, UV 300 nm.

Method R:

XBidge BEHXP C18 (2.1×50 mm) 2.5 micron; Solvent A: 0.1% TFA in 95%water, 5% acetonitrile; Solvent B: 0.1% TFA in 5% water, 95%acetonitrile, Gradient: 0-100% B over 3 minutes; Flow: 1.1 mL/min, UV220 nm.

Method S:

XBidge BEH XP C18 (2.1×50 mm) 2.5 micron; Solvent A: 10 mM ammoniumacetate in 95% water, 5% acetonitrile; Solvent B: 10 mM ammonium acetatein 5% water, 95% acetonitrile, Gradient: 0-100% B over 3 minutes; Flow:1.1 mL/min, UV 220 nm.

Method T:

DAD-1 Kinetix biphenyl (4.6×100 mm) 2.6 micron; Solvent A: 95% water, 5%acetonitrile, 0.05% TFA; Solvent B: 5% water, 95% acetonitrile, 0.05%TFA; Gradient: 0-100% B over 12.5 minutes, then 1.5 minutes hold at 100%B; Flow: 1.0 mL/min, UV 300 nm.

Method U:

DAD-1 Kinetex EVO C18 (4.6×100 mm) 2.6 micron; Solvent A: 95% water, 5%acetonitrile, 0.05% TFA; Solvent B: 5% water, 95% acetonitrile, 0.05%TFA; Gradient: 0-100% B over 12.5 minutes, then 1.5 minutes hold at 100%B; Flow: 1.0 mL/min, UV 300 nm.

SEC and Chiral Purity Methods:

Method I:

Lux Amylose 2 (250×4.6 mm) 5 micron; 0.2% DEA in n-hexane: EtOH: 5:95,Flow: 2.0 mL/min, Temperature: 25° C., UV: 270 nm.

Method II:

Chiralpak AS-H (250×4.6 mm) 5 micron; 0.2% DEA in n-hexane: EtOH: 5:95,Flow: 2.0 mL/min, Temperature: 25° C., UV: 270 nm.

Method III:

Chiralpak IE (250×4.6 mm) 5.0 micron; 0.2% DEA in EtOH, Flow: 1.0mL/min, Temperature: 25° C., UV: 220 nm.

Method IV:

Chiralcel IE (250×4.6 mm) 5 micron; 0.2% DEA in n-hexane: EtOH: 50:50,Flow: 1.0 mL/min, Temperature: 25° C., UV: 260 nm.

Method V:

Chiralpak IB (250×4.6 mm) 5 micron; 0.1% DEA in EtOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 270 nm.

Method VI:

Chiralpak ID (250×4.6 mm) 5 micron; 0.1% DEA in EtOH, Flow: 1.0 mL/min.Temperature: 25° C., UV: 254 nm.

Method VII:

Chiralpak IF (250×4.6 mm) 5 micron; 0.2% DEA in EtOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 254 nm.

Method VIII:

Chiralpak IA (250×4.6 mm) 5 micron; 0.2% DEA in MeOH, Flow: 4.0 mL/min,Temperature: 25° C., UV: 280 nm.

Method IX:

Chiralpak ID (250×4.6 mm) 5 micron; 0.2% TEA in n-hexane: EtOH (10:90)Flow: 1.0 mL/min, Temperature: 25° C., UV: 254 nm.

Method X:

Chiralcel OJ-H (250×4.6 mm) 5 micron; 0.2% DEA in MeOH, Flow: 4.0mL/min, Temperature: 30° C., UV: 296 nm.

Method XI:

Chiralpak IC (250×4.6 mm) 5 micron; 0.1% DEA in MeOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 254 nm.

Method XII:

Chiralpak ADH (250×4.6 mm) 5 micron; 0.2% DEA in MeOH+IP A (1:1), Flow:1.2 mL/min, Temperature: 25° C., UV: 233 nm.

Method XIII:

Chiralpak AS-H (250×4.6 mm) 5 micron; 0.2% DEA in MeOH, Flow: 1.2mL/min, Temperature: 23.3° C., UV: 271 nm.

Method XIV:

Chiralpak IB (250×4.6 mm) 5 micron; 0.2% DEA in MeOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 254 nm.

Method XV:

Chiralpak ID (250×4.6 mm) 5 micron; 0.2% DEA in MeOH, Flow: 1.0 mL/min.Temperature: 25° C., UV: 254 nm.

Method XVI:

Lux Amylose 2 (250×4.6 mm) 5 micron; 0.1% DEA in MeOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 254 nm.

Method XVII:

Chiralpak IF (250×4.6 mm) 5 micron; 0.2% DEA in MeOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 254 nm.

Method XVIII:

Chiralpak IE (250×4.6 mm) 5.0 micron; 0.2% DEA in MOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 220 nm.

Method XIX:

Lux Cellulose 4 (250×4.6 mm) 5.0 micron; 0.1% DEA in EtOH, Flow: 1.0mL/min, Temperature: 25° C., UV: 220 nm.

Method XX:

Chiralcel OD-H (250×4.6 mm) 5 micron; 0.2% DEA in MeOH, Flow: 1.0mL/min, Temperature: 25° C., UV: 220 nm.

Method XXI:

Chiralcel OD-H (250×4.6 mm) 5 micron; 0.2% NH₄OH in MeOH and ACN (1:1),Flow: 4.0 mL/min, Temperature: 30° C., UV: 290 nm.

Method XXII:

Lux Cellulose C2 (250×4.6 mm) 5.0 micron; 0.2% DEA in MeOH, Flow: 1.0mL/min, Temperature: 25° C., UV: 220 nm.

Method XXIII:

Phenomenex IC (250×4.6 mm) 5 micron; 0.2% DEA in EtOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 254 nm.

Method XXIV:

Whelk-1(R,R) (250×4.6 mm) 5 micron; 0.1% DEA in MeOH, Flow: 1.0 mL/min,Temperature: 25° C., UV: 220 nm.

Method XXV:

Cellulose-4 (250×4.6 mm) 5.0 micron; 0.1% DEA in ACN, Flow: 1.0 mL/min,Temperature: 25° C., UV: 254 nm.

Method XXVI:

Chiralpak IC (250×4.6 mm) 5.0 micron; 0.2% ammonia in ACN: MeOH (1:1)Flow: 1.0 mL/min, Temperature: 25° C., UV: 220 nm

Method XXVII:

Chiralpak IC (250×4.6 mm) 5 micron; 0.2% NH₄OH in MeOH+ACN (1:1), Flow:1.2 mL/min. Temperature: 30° C., UV: 235 nm

Method XXVIII:

Lux cellulose-2 (250×4.6 mm) 5 micron; 0.2% NH₄OH in MeOH, Flow: 1.2mL/min. Temperature: 30° C., UV: 240 nm

NMR Employed in Characterization of Examples:

NMR spectra were obtained with Bruker or JEOL Fourier transformspectrometers operating at frequencies as follows: ³H NMR: 400 MHz or300 MHz (Bruker). ¹³C NMR: 100 MHz or 75 MHz (Bruker). Spectral data arereported in the format: chemical shift (multiplicity, couplingconstants, and number of hydrogens). Chemical shifts are specified inppm downfield of a tetramethylsilane internal standard (5 units,tetramethylsilane=0 ppm) and/or referenced to solvent peaks, which in ³HNMR spectra appear at 2.49 ppm for CD₂HSOCD₃, 3.30 ppm for CD₂HOD, and7.24 ppm for CHCl₃, and which in ¹³C NMR spectra appear at 39.7 ppm forCD₃SOCD₃, 49.0 ppm for CD₃OD, and 77.0 ppm for CDCl₃. All ¹³C NMRspectra were proton decoupled.

Intermediate 1-I: (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-oneIntermediate 1-II: (S)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one

Both enantiomers were synthesized according to literature procedures (WO2010/129379).

Intermediate 2-I: (R)-4-methyl-5-(piperazin-2-yl)isobenzofuran-1(3H)-oneIntermediate 2-II:(S)-4-methyl-5-(piperazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 2A: 5-bromo-4-methylisobenzofuran-1(3H)-one

Synthesized according to literature procedures (PCT Int. Appl.,2015095097).

Intermediate 2B4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one

A solution of Intermediate 2A (12.50 g, 55.10 mmol),bispinacolatodiboron (20.97 g, 83.00 mmol) and potassium acetate (16.21g, 165.00 mmol) in dioxane (200 mL) was degassed with nitrogen for 20minutes. PdCl₂(dppf)₂CH₂Cl₂ (4.50 g, 5.51 mmol) was added and theresulting mixture was degassed again for 10 minutes then was heated at100° C. for 12 h. The reaction was cooled to ambient temperature,filtered through Celite® and the filtrate was concentrated under reducedpressure. The resultant residue was washed with n-hexane to obtainIntermediate 2B (8.55 g, 56.70%) as a black solid. The compound wastaken directly to the subsequent step without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.28-1.43 (m, 12H), 2.46 (s, 3H), 5.41 (s,2H), 7.65 (d, J=7.9 Hz, 1H), 7.72-7.87 (m, 1H). LCMS (Method-1):retention time 1.43 min, [M+H] 275.1.

Intermediate 2C: 4-methyl-5-(pyrazin-2-yl)isobenzofuran-1(3H)-one

A solution of 2-chloropyrazine (7.94 g, 69.30 mmol), Intermediate 2B(19.00 g, 69.30 mmol), and potassium phosphate tribasic (36.80 g, 173.00mmol) in a mixture of 1,4-dioxane (100 mL) and H₂O (20 mL) was degassedwith nitrogen for 10 minutes. PdCl₂(dppf)₂CH₂Cl₂ (2.83 g, 3.47 mmol) wasadded and the resulting mixture was degassed again for 10 minutes thenwas heated at 100° C. for 12 h. The reaction mixture was cooled toambient temperature, filtered through the Celite® and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Redisep-330 g, 40% EtOAc/n-hexane) to obtainIntermediate 2C (13.00 g, 83.00%) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.32 (s, 3H), 5.50 (s, 2H), 7.72 (d, J=7.5 Hz, 1H),7.82 (d, J=8.0 Hz, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.77-8.87 (m, 1H), 8.91(d, J=2.0 Hz, 1H). LCMS (Method-H): retention time 1.06 min, [M+H]227.0.

Intermediate 2-I and 2-II

To a stirred solution of Intermediate 2C (13.00 g, 57.50 mmol) in aceticacid (150 mL) was added palladium(II) acetate (1.94 g, 8.62 mmol). Thereaction mixture was stirred under H₂ gas pressure (50 psi) at ambienttemperature for 14 h. The reaction mixture was filtered through Celite®and washed with MeOH. The filtrate was evaporated under reduced pressureand the racemate was separated into two individual enantiomers bysupercritical fluid chromatography (SFC) [Chiralpak ADH (250×4.6 mm) 5micron; 0.2% DEA in MeOH+IPA (1:1), Flow: 1.2 mL/min. Temperature: 23.8°C., UV: 235 nm]. First eluted compound (retention time 2.98 min),designated as Intermediate 2-I, was obtained (4.00 g, 30.00%) as yellowsemi solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H), 2.37-2.39 (m,1H), 2.57-2.68 (m, 2H), 2.71-2.85 (m, 4H), 2.91 (d, J=11.55 Hz, 1H),3.94 (dd, J=9.79, 2.76 Hz, 1H), 5.38 (s, 2H), 7.64 (d, J=8.03 Hz, 1H),7.79 (d, J=8.03 Hz, 1H). LCMS (Method-H) retention time 0.74 min, [M+H]233.0. Chiral purity (Method-XII): retention time 3.00 min, 99.0% ee.SOR: [α]²⁵ _(D)=−52.00 (c 0.05, MeOH). Second eluted compound (retentiontime 3.90 min), designated as Intermediate 2-II, was obtained (4.00 g,30.00%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H),2.37-2.39 (m, 1H), 2.57-2.68 (m, 2H), 2.71-2.85 (m, 4H), 2.91 (d,J=11.55 Hz, 1H), 3.94 (dd, J=9.79, 2.76 Hz, 1H), 5.38 (s, 2H), 7.64 (d,J=8.03 Hz, 1H), 7.79 (d, J=8.03 Hz, 1H). LCMS (Method-H) retention time3.73 min, [M+H] 233.0. Chiral purity (Method-M): retention time 3.73min, 100% ee. SOR: [α]²⁵ _(D)=+62.00 (c 0.05, MeOH).

Intermediate 3-I: (R)-4-methyl-5-(morpholin-2-yl)isobenzofuran-1(3H)-one

Intermediate 3A-1(R)-5-(2-(benzyl(2-hydroxyethyl)amino)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one

To a stirred solution of Intermediate 1-I (1.00 g, 5.26 mmol) in ethanol(5 mL) was added 2-(benzylamino)ethanol (0.75 mL, 5.26 mmol) and theresulting reaction mixture was stirred at 85° C. for 48 h. The reactionmixture was cooled to ambient temperature and concentrated under reducedpressure, diluted with water (30 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was washed with n-hexane (50 mL) to obtainIntermediate 3A-I (1.20 g, 66.90%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.11(s, 3H), 2.56-2.72 (m, 4H), 3.40-3.53 (m, 3H), 3.72 (s, 2H), 4.45-4.51(m, 1H), 4.98 (dd, J=7.53, 4.52 Hz, 1H), 5.27-5.37 (m, 2H), 5.75 (s,3H), 7.18-7.34 (m, 3H), 7.62 (s, 1H). LCMS (Method-H): retention time1.48 min, [M+H] 342.2.

Intermediate 3B-I:(R)-5-(4-benzylmorpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

To a solution of Intermediate 3A-I (1.20 g, 3.51 mmol) in THE (25 mL)was added tri-N-butylphosphine (1.42 g, 7.03 mmol) followed by DIAD(0.82 mL, 4.22 mmol) and the resulting reaction mixture was stirred atambient temperature for 2 h. The reaction mixture was diluted with water(30 mL) and extracted with ethyl acetate (2×40 mL). The combined organiclayers were washed with brine (40 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (Redisep-40 g, 55% EtOAc/n-Hexanes)to afford Intermediate 3B-I (0.75 g, 66.00%). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.18-2.22 (m, 3H), 2.23-2.28 (m, 1H), 2.51-2.56 (m, 1H), 2.75 (d,J=12.55 Hz, 1H), 2.85 (d, J=11.55 Hz, 1H), 3.55 (d, J=5.52 Hz, 2H),3.73-3.80 (m, 1H), 3.99 (dd, J=11.55, 2.01 Hz, 1H), 4.82 (dd, J=10.04,2.51 Hz, 1H), 5.38 (d, J=2.01 Hz, 2H), 7.24-7.29 (m, 1H), 7.34 (d,J=4.52 Hz, 4H), 7.58-7.70 (m, 2H). LCMS (Method-D): retention time 2.74min, [M+H]324.2.

Intermediate 3-I

A solution of Intermediate 3B-I (0.75 g, 2.32 mmol) in ethanol (50 mL)was purged with nitrogen for 2 min. 10% Pd/C (0.25 g, 2.32 mmol) wasadded and the reaction mixture was stirred at ambient temperature for 3h under H₂ atmosphere. The resulting reaction mixture was concentratedunder reduced pressure, diluted with water, neutralized by aq. NaHCO₃and extracted with ethyl acetate (2×25 mL). The combined organic layerswere washed with brine (10 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Alumina-24 g, 5% MeOH/DCM) to obtain Intermediate 3-I(0.25 g, 46.20%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3H), 2.45 (d,J=2.51 Hz, 1H), 2.77-2.81 (m, 2H), 2.93 (dd, J=12.55, 2.51 Hz, 1H),3.63-3.70 (m, 1H), 3.90-3.95 (m, 1H), 4.71 (dd, J=10.04, 2.51 Hz, 1H),5.39 (d, J=3.01 Hz, 2H), 7.60-7.63 (m, 1H), 7.66-7.69 (m, 1H),(Exchangeable proton not observed). LCMS (Method-H): retention time 0.89min, [M+H]234.2.

Intermediate 45-(1-((1H-pyrazol-4-yl)methyl)-4,4-difluoropiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 4Atert-butyl3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-oxopiperidine-1-carboxylate

A solution of 5-bromo-4-methylisobenzofuran-1(3H)-one (1.70 g, 7.53mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.50 g, 12.55 mmol) andCs₂CO₃ (4.91 g, 15.06 mmol) in toluene (50 mL) was degassed withnitrogen for 20 minutes. PdCl₂(dtbpf) (0.81 g, 1.25 mmol) was added andthe resulting mixture was degassed again for 10 minutes and then heatedat 110° C. for 12 h. The reaction mixture was cooled to ambienttemperature, filtered through Celite® and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography (Redisep-24 g, 60% EtOAc/n-hexanes) to obtainIntermediate 4A (0.90 g, 20.77%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.41-1.47 (m, 9H), 2.21 (s, 3H), 2.39-2.48 (m, 1H), 2.65-2.76 (m, 1H),3.47 (br. s., 2H), 4.04-4.21 (m, 3H), 5.41 (d, J=3.01 Hz, 2H), 7.39 (d,J=8.03 Hz, 1H), 7.65 (d, J=8.03 Hz, 1H). LCMS (Method-H): retention time1.92 min, [M+H₂O] 363.2

Intermediate 4B: tert-butyl4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirred solution of Intermediate 4A (0.05 g, 0.14 mmol) in DCM (5mL) at 0° C. was added DAST (0.19 mL, 1.44 mmol) and the reactionmixture was stirred at ambient temperature for 2 h. The resultingreaction mixture was concentrated under reduced pressure, diluted withwater (10 mL), neutralized by aq. NaHCO₃ (10 mL) and extracted with DCM(3×20 mL). The combined organic layer was washed with brine (10 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-12g, 35% EtOAc/n-hexanes) to obtain Intermediate 4B (0.02 g, 37.60%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H), 2.12-2.19 (m, 2H), 2.22 (s,3H), 3.09 (br. s., 1H), 3.37-3.44 (m, 1H), 3.60 (d, J=9.54 Hz, 1H), 3.98(d, J=17.07 Hz, 1H), 4.13 (br. s., 1H), 5.43 (d, J=5.52 Hz, 2H), 7.58(d, J=7.03 Hz, 1H), 7.70 (d, J=8.03 Hz, 1H). ¹⁹F NMR (400 MHz, DMSO-d₆)δ ppm −93.57, −111.02. LCMS (Method-H): retention time 2.45 min, [M+H]368.2.

Intermediate 4C:5-(4,4-difluoropiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

To a solution of Intermediate 4B (0.24 g, 0.65 mmol) in DCM (25 mL) at0° C. was added 4N HCl in dioxane (5 mL, 1.14 mmol). The resultingmixture was stirred at ambient temperature for 2 h. The reaction mixturewas concentrated to dryness and diluted with water (10 mL). The aqueouslayer was washed with ethyl acetate (2×20 mL), basified with 10% NaHCO₃solution and extracted with DCM (3×50 mL). The combined organic layerswere washed with brine (10 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 4C (0.12 g,68.70%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.94-2.12 (m, 2H), 2.29 (s,3H), 2.76 (td, J=12.93, 3.26 Hz, 1H), 2.96-3.06 (m, 2H), 3.14 (d,J=12.05 Hz, 1H), 3.51-3.63 (m, 1H), 5.38-5.43 (m, 2H), 7.52-7.57 (m,1H), 7.67 (d, J=8.03 Hz, 1H) (Exchangeable proton not observed). ¹⁹F NMR(400 MHz, DMSO-d₆) δ ppm−88.62, −110.24. LCMS (Method-H): retention time1.34 min, [M+H] 268.0.

Intermediate 4

To a solution of Intermediate 4C (0.10 g, 0.37 mmol) in MeOH (2 mL) wasadded 1H-pyrazole-4-carbaldehyde (0.030 g, 0.37 mmol) and the reactionmixture was stirred at ambient temperature for 15 min. To this mixturewas added NaCNBH₃ (0.071 g, 1.12 mmol) and stirring was continued for 12h. The reaction mixture was diluted with water (15 mL) and extractedwith DCM (3×20 mL). The combined organic layer was washed with brine (20mL), dried over anhydrous sodium sulfate and evaporated under reducedpressure. The resulting residue was washed with diethyl ether (20 mL) toobtain Intermediate 4 (0.08 g, 61.60%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.08-2.18 (m, 2H) 2.23 (s, 3H) 2.76 (d, J=11.04 Hz, 1H) 2.86 (d, J=11.55Hz, 1H) 3.45 (s, 2H) 3.65-3.80 (m, 2H) 4.78 (d, J=8.03 Hz, 1H) 5.33-5.43(m, 2H) 7.41 (br. s., 1H) 7.52-7.71 (m, 3H) 12.64 (br. s., 1H). LCMS(Method-H): retention time 1.121 min, [M+H] 348.2.

Intermediate 5-I:(R)-5-(4-((6-bromopyridin-3-yl)methyl)morpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 5-I was prepared (0.25 g, 72.30%), by using a similarsynthetic protocol as that of Intermediate 4 and starting from6-bromonicotinaldehyde (0.15 g, 0.85 mmol) and Intermediate 3-I LCMS(Method-1): retention time 0.68 min, [M+H] 403.0. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 6: 6-(4-formyl-1H-pyrazol-1-yl)nicotinonitrile

To a stirred solution of 1H-pyrazole-4-carbaldehyde (1.00 g, 10.40 mmol)and 6-bromo-4-methylnicotinonitrile (2.05 g, 10.40 mmol) in dioxane (15mL) were added K₂CO₃ (4.31 g, 31.20 mmol). The resulting reactionmixture was degassed with nitrogen for 5 minutes then copper (I) iodide(0.59 g, 3.12 mmol) was added, followed bytrans-N,N′-dimethylcyclohexane-1,2-diamine (2.59 mL, 16.4 mmol). Theresulting mixture was degassed again for 10 minutes and heated at 110°C. for 1 h under microwave irradiation. The reaction mixture was cooledto ambient temperature, filtered through Celite® and the organic layerwas concentrated under reduced pressure. The residue was purified bycolumn chromatography (Redisep-24 g, 20-40% EtOAc/n-hexane) to obtainIntermediate 6 (1.15 g, 52.10%) as pale yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.62 (s, 3H), 8.10 (s, 1H), 8.38 (s, 1H), 8.95 (s, 1H),9.37 (s, 1H), 9.98 (s, 1H). LCMS (method-D), retention time 1.68 min,[M+H] 213.2.

Intermediate 7: 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one

Synthesized according to literature procedures (PCT Int. Appl.,2010130773).

Intermediate 8:3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one

Intermediate 8 was prepared (1.30 g, 59.80%) as a yellow solid, by usingIntermediate 7 (1.50 g, 6.44 mmol) in a manner similar to that describedfor Intermediate 2A. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31 (s, 12H), 3.37(s, 3H), 7.34 (d, J=7.93 Hz, 1H), 7.41-7.54 (m, 2H). LCMS (Method-D):retention time 2.79 min, [M−H] 292.2 (water adduct).

Intermediate 9:6-(4-formyl-5-methoxy-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 9A: dimethyl 2-((dimethylamino)methylene)malonate

To a solution of dimethyl malonate (10.00 g, 76.00 mmol) in toluene (100mL) was added DMF-DMA (20.27 mL, 151.00 mmol) at ambient temperatureunder a nitrogen atmosphere. The resulting reaction mixture was heatedat 100° C. for 5 h. The reaction mixture was cooled to ambienttemperature and concentrated under reduced pressure to obtainIntermediate 9A (13.00 g, 84.00%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 2.92-3.07 (m, 6H), 3.66-3.72 (br.s., 3H), 3.74-3.79 (br.s.,3H), 7.53 (s, 1H). LCMS (Method-D): retention time 0.63 min, [M+H]188.2. The compound was taken directly to the subsequent step withoutfurther purification or characterization.

Intermediate 9B: methyl 5-methoxy-1H-pyrazole-4-carboxylate

To a solution of Intermediate 9A (13.00 g, 69.40 mmol) in EtOH (50 mL)was added NH₂NH₂.2HCl (7.29 g, 69.40 mmol) at ambient temperature undera nitrogen atmosphere. The resulting reaction mixture was heated at 70°C. for 5 h. The reaction mixture was cooled to ambient temperature andconcentrated under reduced pressure. The residue was dissolved in DCM(250 mL) and basified with saturated NaHCO₃ solution (0.5 L). Theorganic layer was separated, washed with brine (20 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-120 g, 45-50%EtOAc/n-hexanes) to obtain Intermediate 9B (2.50 g, 13.14%) as a paleyellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.67 (s, 3H), 3.84 (s,3H), 8.11 (d, J=2.27 Hz, 1H), 12.56 (br. s., 1H). LCMS (Method-D):retention time 0.48 min, [M+H] 157.0.

Intermediate 9C: methyl1-(5-cyano-4-methylpyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylate

Intermediate 9C was prepared (0.80 g, 15.42%) as a beige solid, using asimilar synthetic protocol to that of Intermediate 6 and starting fromIntermediate 9B (2.50 g, 16.01 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.64(s, 3H), 3.87 (s, 3H), 4.11 (s, 3H), 7.81 (d, J=1.00 Hz, 1H), 8.57 (s,1H), 8.89 (s, 1H). LCMS (Method-H): retention time 1.81 min, [M+H] 273.

Intermediate 9_(D):1-(5-cyano-4-methylpyridin-2-yl)-5-methoxy-1H-pyrazole-4-carboxylicacid

To a solution of Intermediate 9C (0.80 g, 2.94 mmol) in THF (25 mL) wasadded (CH₃)₃SiOK (1.50 g, 11.75 mmol) and stirring was continued atambient temperature for 16 h. The reaction mixture was diluted withwater (80 mL), neutralized with solid citric acid and extracted withethyl acetate (2×80 mL). The combined organic layers were washed withbrine (30 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure to obtain Intermediate 9_(D) (0.75 g, 61.30%) as beigesolid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.59 (s, 3H), 4.00 (s, 3H), 7.86(s, 1H), 8.78 (s, 1H), 8.85 (s, 1H), 12.37-12.91 (br. s, 1H). LCMS(Method-H): retention time 0.40 min, [M+H] 259.5.

Intermediate 9E:6-(4-(hydroxymethyl)-5-methoxy-1H-pyrazol-1-yl)-4-methylnicotinonitrile

To a solution of Intermediate 9_(D) (0.75 g, 2.90 mmol) in THF (15 mL)was added TEA (1.21 mL, 8.71 mmol) followed by isobutyl chloroformate(0.76 mL, 5.81 mmol) at 0° C. under a nitrogen atmosphere. The reactionmixture was stirred at ambient temperature for 16 h. The reactionmixture was filtered through a scintered glass funnel and the filtratewas cooled to 0° C. and treated with a solution of NaBH₄ (0.22 g, 5.81mmol) in water (2 mL) for 10 minutes. The resultant mixture was allowedto reach ambient temperature and stir for 16 h. The reaction mixture wasdiluted with saturated NH₄Cl (40 mL) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with 10% NaHCO₃solution (30 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain Intermediate 9E (0.43 g, 53.30%) asbeige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54 (s, 3H), 3.96 (s, 3H),4.30 (d, J=5.02 Hz, 2H), 4.97 (t, J=5.52 Hz, 1H), 7.72 (s, 1H), 8.37 (s,1H), 8.75 (s, 1H). LCMS (Method-D): retention time 1.681 min, [M+H]245.0.

Intermediate 9

To a solution of Intermediate 9E (0.40 g, 1.64 mmol) in DCM (30 mL) wasadded Dess-Martin periodinane (1.39 g, 3.28 mmol) at ambient temperatureunder a nitrogen atmosphere and stirring was continued for 20 h. Thereaction mixture was diluted with DCM (50 mL) and 10% NaHCO₃ (50 mL) wasadded. The organic layer was separated and washed with brine (30 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain Intermediate 9 (0.30 g, 68.10%) as beige solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.61 (s, 3H), 4.05 (s, 3H), 7.91 (s, 1H),8.90 (s, 1H), 9.18 (s, 1H), 9.85 (s, 1H). LCMS (Method-H): retentiontime 2.13 min, [M+H] 243.0.

Intermediate 10: 6-bromo-4-cyclopropylnicotinonitrile

Intermediate 10A: 6-bromo-4-iodonicotinonitrile

To a solution of diisopropylamine (7.79 mL, 54.60 mmol) in THE (100 mL)was added n-BuLi (21.86 mL, 54.60 mmol) at −78° C. under a nitrogenatmosphere. After 30 minutes, 6-bromonicotinonitrile (10.00 g, 54.6mmol) in THE (20 mL) followed by Iodine (15.26 g, 60.10 mmol) in THE (10mL) was added and stirring was continued for 2 h. The resulting reactionmixture was diluted with saturated NH₄Cl (40 mL) and extracted withethyl acetate (2×200 mL). The combined organic layer was washed withbrine solution (30 mL), dried over anhydrous sodium sulfate, andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep-80 g, 10-15% EtOAc/n-Hexanes) to obtainIntermediate 10A (6.50 g, 38.50%) as brown solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.51 (s, 1H), 8.76 (s, 1H). LCMS: The compound did notionize well.

Intermediate 10

To a solution of Intermediate 10A (0.60 g, 1.94 mmol) in a mixture oftoluene (10 mL) and water (2 mL) was added cyclopropylboronic acid (0.20g, 2.33 mmol) followed by K₃PO₄ (0.82 g, 3.88 mmol) and the resultingmixture was degassed for 15 minutes. Palladium(II) acetate (0.05 g, 0.19mmol) and tricyclohexylphosphine (0.11 g, 0.39 mmol) ware added. Theresulting mixture was degassed again for 10 minutes and heated at 140°C. for 1 h in the microwave. The reaction mixture was cooled to ambienttemperature and filtered through Celite®. The filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography (Redisep-12 g, 15-20% EtOAc/n-Hexanes) to obtainIntermediate 10 (0.10 g, 23.08%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.93-1.02 (m, 1H), 1.04-1.13 (m, 1H), 1.19-1.35 (m, 2H),2.05-2.21 (m, 1H), 8.51 (s, 1H), 8.75 (s, 1H). LCMS (Method-D):retention time 2.25 min, [M+2H] 223.0.

Intermediate 11: 6-(4-formyl-1H-imidazol-1-yl)-4-methoxynicotinonitrile

To a solution of 1H-imidazole-4-carbaldehyde (0.50 g, 5.20 mmol) and6-chloro-4-methoxynicotinonitrile (1.05 g, 6.24 mmol) in DMF (10 mL) wasadded K₂CO₃ (1.08 g, 7.81 mmol) at ambient temperature under a nitrogenatmosphere. The resulting reaction mixture was heated at 90° C. for 1 h.The reaction mixture was cooled to ambient temperature and diluted withice water (30 mL). The resulting precipitate was filtered and was washedwith ethanol (2 mL) to obtained Intermediate 11 (0.30 g, 25.00%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 4.13 (s, 3H), 7.81 (s, 1H), 8.83 (s, 2H), 8.95(d, J=1.19 Hz, 1H), 9.87 (s, 1H). LCMS (Method-L): retention time 0.75min, [M+H] 229.1.

Intermediate 12-I:(R)-6-(4-(((2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)amino)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 12A-I:(R)-5-(2-amino-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one

To a solution of Intermediate 1-I (1.00 g, 5.26 mmol) in MeOH (40 mL) at−10° C. was purged excess of ammonia gas and the resulting reactionmixture was stirred at 50° C. for 16 h in a sealed tube. The reactionmixture was concentrated under reduced pressure and the residue waswashed with ether (30 mL) to obtain Intermediate 12A-I (0.75 g, 68.80%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H), 2.52-2.56 (m, 1H), 2.69(dd, J=13.05, 4.02 Hz, 1H), 4.80 (dd, J=8.03, 3.51 Hz, 1H), 5.38 (d,J=1.51 Hz, 3H), 7.65 (s, 2H), (2 Exchangeable protons not observed).LCMS (Method-H): retention time 0.54 min, [M+H] 208.2.

Intermediate 12-I

To a solution of Intermediate-6 (0.20 g, 0.94 mmol) in MeOH (5 mL) wasadded acetic acid (0.08 mL, 1.42 mmol) followed by Intermediate 12A-I(0.23 g, 1.13 mmol) and the reaction mixture was stirred at ambienttemperature for 10 minutes. To the reaction was added NaCNBH₃ (0.18 g,2.83 mmol) and stirring was continued for 12 h. The reaction mixture wasdiluted with water (20 mL), basified with 10% NaHCO₃ solution andextracted with ethyl acetate (2×30 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by HPLC[Luna C18 (250×30ID) 5 micron; Solvent A: 0.1% TFA in H₂O, Solvent B:Acetonitrile, Gradient: 20-100 over 14 min, Flow: 25 mL/min, retentiontime 11.16 min, UV 220 nm] to obtain Intermediate 12-I (0.09 g, 22.86%).H NMR (400 MHz, CDCl₃) δ ppm 2.28 (s, 3H), 2.63 (s, 3H), 2.77-2.67 (m,1H), 3.03-2.93 (m, 1H), 3.62 (m, 2H), 3.86 (d, J=6.00 Hz, 2H), 5.10-5.03(m, 1H), 5.25 (s, 2H), 7.80-7.74 (m, 3H), 7.95 (d, J=0.80 Hz, 1H), 8.49(d, J=0.80 Hz, 1H), 8.59 (s, 1H). LCMS/HPLC (Method-H): retention time1.80 min, [M+H] 404.2, purity: 99.7%. (Method-C): retention time 10.54min, purity: 99.70%. Chiral purity (Method-VI): retention time 9.44 min,100% ee.

Intermediate 13-I:(R)—N-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-2-hydroxy-N-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)acetamide

To a stirred solution of Intermediate 12-I (0.23 g, 0.57 mmol) and2-hydroxyacetic acid (0.05 g, 0.57 mmol) in DCM (10 mL) was added HA TU(0.43 g, 1.14 mmol) followed by DTPEA (0.29 mL, 1.71 mmol). Theresultant mixture was stirred at ambient temperature overnight. Water(30 mL) was added to the reaction mixture, which was then extracted withDCM (3×20 mL). The combined organic layers were washed with brine (20mL), dried over sodium sulfate and evaporated under reduced pressure.The residue was purified by column chromatography (Redisep-12 g, 10-12%MeOH in DCM), to obtain Intermediate 13-I (0.15 g, 57.00%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21-2.35 (m, 3H), 2.58(s, 3H), 3.14-3.29 (m, 1H), 3.37-3.68 ((m, 1H), 4.10-4.36 (m, 2H),4.41-4.78 (m, 3H), 5.08-5.30 (m, 1H), 5.31-5.45 (m, 2H), 5.66-5.92 (m,1H), 7.61-7.77 (m, 2H), 7.84 (s, 1H), 7.94-8.02 (m, 1H), 8.57 (s, 1H),8.84 (s, 1H). LCMS/HPLC (Method-A): retention time 1.382 min, [M+H]462.1, purity: 98.52%. (Method-B): retention time 1.372 min, [M+H]462.1, purity: 99.62%.

Intermediate 14-I(R)-5-(4-((1H-pyrazol-4-yl)methyl)morpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 14-I was prepared (0.75 g, 27.90%), by using a similarsynthetic protocol as that of Intermediate 4 and starting fromIntermediate 3-I (2.00 g, 8.57 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.78-1.87 (m, 1H), 2.11-2.20 (m, 1H), 2.23 (s, 3H), 2.76 (d, J=11.04 Hz,1H), 2.86 (d, J=11.55 Hz, 1H), 3.45 (s, 2H), 3.67-3.79 (m, 1H), 3.97 (d,J=9.54 Hz, 1H), 4.78 (d, J=8.03 Hz, 1H), 5.38 (d, J=2.01 Hz, 2H), 7.41(br. s., 1H), 7.57-7.62 (m, 2H), 7.64-7.69 (m, 1H), 12.64 (br. s., 1H).LCMS/HPLC (Method-H): retention time 0.767 min, [M+H] 314.2.

Intermediate 15:4-methoxy-6-(4-(2-oxoethyl)-1H-pyrazol-1-yl)nicotinonitrile

Intermediate 15A: 3-(diethoxymethyl)-2-ethoxytetrahydrofuran

FeCl₃ (0.02 g, 0.14 mmol) was added to a flask containingtriethoxymethane (23.26 g, 157.00 mmol) and cooled to 10° C. Theresulting reaction mixture was stirred at the same temperature for 30minutes and 2,3-dihydrofuran (10.00 g, 143.00 mmol) was added dropwiseover 30 minutes. The reaction mixture was stirred at 10° C. for 1 h,diluted with DCM (100 mL) and filtered through Celite®. The filtrate wasconcentrated under reduced pressure to obtain Intermediate 15A (30.00 g,96.00%) as brown oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.09-1.29 (m, 9H),1.76 (dd, J=12.55, 5.52 Hz, 1H), 1.84-2.13 (m, 1H), 2.29-2.57 (m, 1H),3.38-3.81 (m, 6H), 3.82-4.14 (m, 2H), 4.33 (d, J=8.53 Hz, 1H), 4.88-5.09(m, 1H).

Intermediate 15B: 2-(1H-pyrazo-4-yl)ethanol

To a solution of NH₂NH₂ 2HCl (18.75 g, 179.00 mmol) in a mixture ofwater (50 mL) and ethanol (25 mL) was added Intermediate 15A (30.00 g,137.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hand at ambient temperature for 1 h. Sodium carbonate (30.00 g) was addedto the reaction mixture and evaporated to dryness under reducedpressure. The residue was washed with ethanol (100 mL) and evaporated toobtain Intermediate 15B (15.00 g, 92.00%) as a brown oil. ¹H NMR (400MHz, CDCl₃) δ ppm 2.78 (t, J=6.38 Hz, 2H), 3.72 (d, J=7.25 Hz, 1H),3.77-3.88 (m, 2H), 7.49 (s, 2H), 9.52-10.74 (m, 1H). LCMS (Method-1):retention time 0.40 min, [M+H] 113.0.

Intermediate 15C6-(4-(2-hydroxyethyl)-1H-pyrazol-1-yl)-4-methoxynicotinonitrile

To a solution of Intermediate 15B (0.50 g, 4.46 mmol) and6-bromo-4-methoxynicotinonitrile (0.95 g, 4.46 mmol) in dioxane (20 mL)was added K₂CO₃ (1.54 g, 11.15 mmol) and XANTPHOS (0.52 g, 0.89 mmol)and the resulting reaction mixture was degassed with nitrogen for 5minutes. Pd₂(dba)₃(0.41 g, 0.45 mmol) was added and the resultingmixture was degassed again for 5 minutes then heated at 100° C. for 16h. The reaction mixture was cooled to ambient temperature, filteredthrough Celite® and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography (Redisep-24g, 2-2.5% MeOH in DCM), to obtain Intermediate 15C (0.40 g, 36.70%) as apale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.65 (t, J=6.78 Hz,2H), 3.61 (td, J=6.78, 5.02 Hz, 2H), 4.10 (s, 3H), 4.62-4.76 (m, 1H),7.58 (s, 1H), 7.81 (s, 1H), 8.47 (s, 1H), 8.73 (s, 1H). LCMS (Method-1):retention time 0.83 min, [M+H] 245.3.

Intermediate 15

To a stirred solution of Intermediate 15C (0.20 g, 0.82 mmol) in DCM (10mL) was added Dess-Martin periodinane (0.52 g, 1.23 mmol) and thereaction mixture was stirred at ambient temperature for 10 minutes. Thereaction mixture was diluted with 10% NaHCO₃ (30 mL) and extracted withDCM (3×25 mL). The combined extracts were washed with brine (20 mL),dried over sodium sulfate and evaporated under reduced pressure toobtain Intermediate 15 (0.20 g, 45.32%). LCMS (Method-1): retention time0.95 min, [M+H] 243.0. The compound was taken directly to the subsequentstep without further purification or characterization.

Intermediate 16:6-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile

Intermediate 16A: methyl 5-cyanopicolinate

To a stirred solution of 6-bromonicotinonitrile (3.00 g, 16.39 mmol) inMeOH (80 mL) and DMF (80 mL) was added PdCl₂(dppf)-CH₂Cl₂(2.68 g, 3.28mmol) and TEA (5.71 mL, 41.00 mmol). The resultant mixture was heated at60° C. under an atmosphere of CO (50 psi pressure) for 14 h. Thereaction mixture was cooled to ambient temperature and filtered throughCelite®. The filtate was concentrated under reduced pressure. Theresidue obtained was purified by column chromatography (Redisep—40.00 g,60% EtOAc/n-Hexanes) to obtain Intermediate 16A (2.25 g, 85.00%) as anoff white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.93 (s, 3H), 8.20 (dd,J=8.03, 1.00 Hz, 1H), 8.54 (dd, J=8.03, 2.01 Hz, 1H), 9.09-9.25 (m, 1H).LCMS (Method-L): retention time 0.70 min, [M+H] 163.1.

Intermediate 16B: 5-cyanopicolinohydrazide

To a stirred solution of Intermediate 16A (2.25 g, 13.88 mmol) in EtOH(50 mL) was added hydrazine hydrate (3.39 mL, 69.40 mmol). The reactionmixture was stirred at 80° C. for 14 h then cooled to ambienttemperature. The resultant precipitate was filtered and washed with EtOH(30 mL) to obtain Intermediate 16B (1.90 g, 84.00%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.68 (d, J=4.02 Hz, 2H), 7.91-8.23 (m, 1H),8.42-8.61 (m, 1H), 8.92-9.24 (m, 1H), 10.21 (br. s., 1H). LCMS(Method-L): retention time 0.45 min, [M+H] 163.1.

Intermediate 16

To a stirred solution of Intermediate 16B (1.00 g, 6.17 mmol) in POCl₃(15 mL) was added 2-chloroacetic acid (0.58 g, 6.17 mmol). The resultingreaction mixture was refluxed at 100° C. for 14 h then was cooled toambient temperature. POCl₃ was evaporated under reduced pressure and themixture was diluted with ice water (100 mL). The acidic solution wasbasified by slow addition of solid NaHCO₃ and extracted with ethylacetate (3×50 mL). The combined organic extracts were washed with brine(50 mL), dried over sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-40g, 20% EtOAc/n-Hexane) to obtain Intermediate 16 (0.25 g, 18.37%) as anyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.20 (s, 2H), 8.38 (dd,J=8.53, 1.00 Hz, 1H), 8.55-8.64 (m, 1H), 9.24 (dd, J=2.01, 1.00 Hz, 1H).(Method-1): retention time 0.84 min, [M+H] 221.4.

Intermediate 17:6-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-4-methylnicotinonitrile

Intermediate 17A: methyl 5-cyano-4-methylpicolinate

Intermediate 17A was prepared (1.05 g, 39.10%) as an off white solid, byusing a similar synthetic protocol as that of Intermediate 16A andstarting from 6-bromo-4-methylnicotinonitrile (3.00 g, 15.23 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.60 (s, 3H), 3.92 (s, 3H), 7.85-8.33 (m,1H), 9.04 (s, 1H). (Method-1): retention time 0.76 min, [M+H] 177.2.

Intermediate 17B: 5-cyano-4-methylpicolinohydrazide

Intermediate 17B was prepared (0.45 g, 82.00%) as white solid, by usinga similar synthetic protocol as that of Intermediate 16B and startingfrom Intermediate 17A (0.55 g, 3.12 mmol). ¹H NMR (300 MHz, DMSO-d₆) δppm 2.59 (s, 3H), 4.67 (br. s., 2H), 8.07 (s, 1H), 8.74-9.05 (m, 1H),10.15 (br. s., 1H). (Method-1): retention time 0.51 min, [M+H] 177.2.

Intermediate 17

Intermediate 17 was prepared (0.20 g, 25.03%) as yellow solid, by usinga similar synthetic protocol as that of Intermediate 16 and startingfrom Intermediate 17B (0.60 g, 3.41 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.64 (s, 3H), 5.20 (s, 2H), 8.36 (s,1H), 9.13 (s, 1H). (Method-1): retention time 0.93 min, [M−H] 232.9.

Intermediate 18-I: tert-butyl(R)-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

Intermediate 18A-II:(S)-5-(2-amino-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one

Intermediate 18A-II was prepared (40.00 g, 68.80%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 12A-I andstarting from Intermediate 1-II (40.00 g, 210.00 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.26 (s, 3H), 2.52-2.56 (m, 1H), 2.69 (dd, J=13.05, 4.02Hz, 1H), 4.80 (dd, J=8.03, 3.51 Hz, 1H), 5.38 (d, J=1.51 Hz, 3H), 7.65(s, 2H). (2 Exchangeable protons not observed). LCMS (Method-H):retention time 0.54 min, [M+H] 208.2.

Intermediate 18B-II: tert-butyl(S)-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

A stirred solution of Intermediate 18A-II (40.00 g, 145.00 mmol) in DCM(400 mL) was cooled to 0° C. TEA (60.50 mL, 434.00 mmol) followed byBOC₂O (40.30 mL, 174.00 mmol) were added. The resulting reaction mixturewas stirred at ambient temperature overnight, diluted with water (200mL) and extracted with DCM (3×200 mL). The combined organic layers werewashed with brine (150 mL), dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by columnchromatography (Redisep-750 g, 2% MeOH in chloroform) to obtainIntermediate 18B-II: (48.00 g, 80.00%) as a colorless oil. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.35 (s, 9H), 2.29 (s, 3H), 2.96 (ddd, J=13.70,7.90, 6.00 Hz, 1H), 3.20-3.06 (m, 1H), 4.89-5.02 (m, 1H), 5.38 (s, 2H),5.54 (d, J=4.50 Hz, 1H), 6.89 (t, J=5.80 Hz, 1H), 7.66 (s, 2H). LCMS(Method-1): retention time 0.93 min, [M+H] 308.4.

Intermediate 18C-I: tert-butyl(R)-(2-(1,3-dioxoisoindolin-2-yl)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

To a stirred solution of Intermediate 18B-II (47.00 g, 113.00 mmol) inTHE (800 mL) were added triphenylphosphine (65.30 g, 249.00 mmol)followed by DIAD (39.60 mL, 204.00 mmol). The resulting reaction mixturewas stirred at ambient temperature for 2 h, diluted with water (1.5 L)and extracted with ethyl acetate (3×500 mL). The combined organic layerswere washed with brine (300 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (Redisep—1.5 kg, 40% EtOAc/n-hexane) to obtainIntermediate 18C-I (50.00 g, 91.00%) as a colorless oil. ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.19-1.33 (m, 9H), 2.28 (s, 3H), 3.63 (dt, J=13.79,5.57 Hz, 1H), 3.94-4.15 (m, 1H), 5.26-5.46 (m, 2H), 5.65 (dd, J=9.44,4.15 Hz, 1H), 7.23 (s, 1H), 7.71 (d, J=8.31 Hz, 1H), 7.78-7.94 (m, 5H).LCMS (Method-1): retention time 1.23 min, [M+H] 437.2.

Intermediate 18-I

To a stirred solution of Intermediate 18C-I (40.00 g, 92.00 mmol) inMeOH (500 mL) was added hydrazine hydrate (44.80 mL, 916.00 mmol). Theresulting reaction mixture was heated at 60° C. for 14 h, cooled toambient temperature and diluted with ethyl acetate (200 mL). Theresultant solid was filtered and the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (Redisep—330 g, 2% MeOH/chloroform) to obtainIntermediate 18-I (28.50 g, 91.00%) as a greenish oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.35 (s, 9H), 1.87-2.01 (m, 2H), 2.29 (s, 3H), 2.85-2.97(m, 1H), 3.10 (dd, J=12.30, 6.27 Hz, 1H), 4.24-4.34 (m, 1H), 5.37 (s,2H), 6.87-6.98 (m, 1H), 7.64 (d, J=8.03 Hz, 1H), 7.75 (d, J=8.03 Hz,1H). LCMS (Method-1): retention time 0.84 min, [M+H] 307.1.

Intermediate 19-I:(R)—N-(2-amino-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-chloroacetamide

Intermediate 19A-I: tert-butyl(R)-(2-(2-chloroacetamido)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

To a stirred solution of Intermediate 18-I (0.50 g, 1.63 mmol) in DCM(20 mL) at 0° C. was added TEA (0.68 mL, 4.90 mmol) followed bychloroacetyl chloride (0.13 mL, 1.63 mmol). The resulting reactionmixture was stirred at ambient temperature for 14 h, diluted with water(30 mL) and extracted with DCM (3×30 mL). The combined organic extractswere washed with brine (30 mL), dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by columnchromatography (Redisep-12 g, 2% MeOH in chloroform) to obtainIntermediate 19A-I (0.40 g, 64.00%) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.34 (s, 9H), 2.34 (s, 3H), 3.15-3.26 (m, 2H), 4.08(s, 2H), 5.25 (q, J=7.36 Hz, 1H), 5.34-5.45 (m, 2H), 7.00 (t, J=5.77 Hz,1H), 7.54 (d, J=8.03 Hz, 1H), 7.68 (d, J=8.03 Hz, 1H), 8.76 (d, J=7.53Hz, 1H). (Method-H): retention time 1.53 min, [M+H)] 383.0.

Intermediate 19-I

To a stirred solution of Intermediate 19A-I (0.05 g, 0.13 mmol) in DCM(10 mL) was added TFA (1.00 ml, 12.98 mmol) and reaction mixture wasstirred at ambient temperature for 30 minutes. The reaction mixture wasconcentrated to dryness under reduced pressure. The residue wasdissolved in MeCN (10 mL), water (0.3 mL) and Na₂CO₃ (0.07 g, 0.65 mmol)was added and the reaction mixture was heated at 80° C. for 1 h. Thereaction mixture was cooled to ambient temperature and excess solidsodium carbonate was filtered off. The filtrate was dried over sodiumsulfate and concentrated under reduced pressure to obtain Intermediate19-I (0.04 g, 95.00%) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.36 (s, 3H), 3.04-3.27 (m, 2H), 4.04-4.23 (m, 2H), 5.37-5.53 (m, 3H),7.61 (d, J=8.03 Hz, 1H), 7.76 (d, J=8.03 Hz, 1H), 8.01 (br. s., 2H),8.91 (d, J=8.53 Hz, 1H). (Method-1): retention time 0.53 min, [M−1]281.3.

Intermediate 20: 6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

To a stirring solution of 6-bromonicotinaldehyde (1.25 g, 6.72 mmol) inDMF (10 mL) was added K₂CO₃ (2.32 g, 16.80 mmol) and4-methyl-1H-imidazole (0.55 g, 6.72 mmol). The resulting mixture washeated at 100° C. for 1 h then cooled to ambient temperature. Thereaction was poured into ice water (30 mL) and extracted with ethylacetate (2×75 mL). The combined organic layers were washed with brine(50 mL), dried over sodium sulfate and evaporated under reducedpressure. The residue was purified by flash chromatography (Redisep-40g, 0-100% EtOAc/n-Hexane)) to obtain Intermediate 20 (0.50 g, 39.70%) aslight brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50 (s, 3H), 7.76(s, 1H), 7.95 (dd, J=6.00, 1.20 Hz, 1H), 8.39 (dd, J=6.60, 1.80 Hz, 1H),8.55 (d, 1.20 Hz, 1H), 8.99 (s, 1H), 10.08 (s, 1H), LCMS: (Method-H)retention time: 1.03 min, [M+1]: 188.0.

Intermediate 21: 1-(5-formypyridin-2-yl)-1H-imidazole-4-carbonitrile

Intermediate 21 was prepared (0.40 g, 37.50%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 6-bromonicotinaldehyde (1.00 g, 5.38 mmol) and1H-imidazole-4-carbonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.11 (d,J=8.53 Hz, 1H), 8.53 (dd, J=8.28, 2.26 Hz, 1H), 8.89 (d, J=1.51 Hz, 1H),9.03 (d, J=1.51 Hz, 1H), 9.05-9.10 (m, 1H), 10.14 (s, 1H). LCMS/HPLC:(Method-H) retention time 0.85 min, [M+1]: 199.2.

Intermediate 22: 6-(3-methyl-1H-1,2,4-triazol-1-yl)nicotinaldehyde

Intermediate 22 was prepared (0.30 g, 59.30%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 6-bromonicotinaldehyde (0.50 g, 2.69 mmol) and3-methyl-1H-1,2,4-triazole (0.33 g, 4.03 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.42 (s, 3H), 7.99 (d, J=8.53 Hz, 1H), 8.47 (dd, J=8.53,2.01 Hz, 1H), 9.02-9.04 (m, 1H), 9.37 (s, 1H), 10.12 (s, 1H). LCMS/HPLC:(Method-H) retention time 0.88 min, [M+1]: 189.0.

Intermediate 23-I:(R)-5′-(((2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)amino)methyl)-4-methoxy-[2,2′-bipyridine]-5-carbonitrile

Intermediate 23A: 4-methoxy-6-(trimethylstannyl)nicotinonitrile

A solution of 6-chloro-4-methoxynicotinonitrile (2.00 g, 11.86 mmol) indioxane (10 mL) was degassed with nitrogen for 20 minutes.Hexamethylditin (2.71 mL, 13.05 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium (II) chloride (0.77g, 1.19 mmol) were added. The resulting reaction mixture was degassedagain for 10 minutes, heated at 100° C. for 12 h and was cooled toambient temperature. The reaction mixture was filtered through Celite®and the filtrate was concentrated under reduced pressure to obtainIntermediate 23A: (5.00 g, 39.50%) as a dark oil. LCMS (Method-1):retention time 1.26 min, [M+H] 299.1. The compound was taken directly tothe subsequent step without further purification or characterization.

Intermediate 23B: 5′-formyl-4-methoxy-[2,2′-bipyridine]-5-carbonitrile

A solution of 6-bromonicotinaldehyde (1.10 g, 5.91 mmol) andIntermediate 23A (4.83 g, 6.51 mmol) in dioxane (20 mL) was degassedwith nitrogen for 20 minutes. To the stirring solution was addedtetrakistriphenylphospine palladium (0.68 g, 0.59 mmol) followed bycopper (I) iodide (0.11 g, 0.59 mmol) and the resulting mixture wasdegassed again for 10 minutes. The resulting reaction mixture was heatedat 100° C. for 16 h then cooled to ambient temperature and filteredthrough Celite®. The filtrate was concentrated under reduced pressure.The residue was purified by column chromatography (Redisep-40 g, 0-40%EtOAc/n-Hexane) to obtain Intermediate 23B (1.60 g, 79.00%) as off-whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.16 (s, 3H), 8.22 (d, J=14.35Hz, 1H), 8.46 (d, J=8.31 Hz, 1H), 8.55-8.72 (m, 1H), 8.99 (d, J=1.51 Hz,1H), 9.24 (s, 1H), 10.20 (s, 1H). LCMS/HPLC: (Method H) retention time:1.63 min, [M+1]: 240.0.

Intermediate 23-I

To a solution of Intermediate 23B (0.60 g, 1.75 mmol) in a mixture ofDCM (20 mL) and MeOH (6 mL) were added 12A-I (0.36 g, 1.75 mmol)followed by AcOH (0.40 mL, 7.02 mmol). The resulting reaction mixturewas stirred at ambient temperature for 2 h followed by the addition ofNaBH(CH₃CO₂)₃ (0.37 g, 1.75 mmol). Stirring was continued for 12 h. Thereaction was then diluted with water (15 mL) and extracted with DCM(2×100 mL). The combined organic layer was washed with brine (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by prep HPLC [Symmetry C8 (300×19 ID)9 micron; Solvent A: 10 mM ammonium acetate, Solvent B: Acetonitrile,Gradient: 0-100% B over 21 min, Flow: 18 mL/min, retention time 12.50min, UV 220 nm] to obtain Intermediate 23-I (0.10 g, 13.76%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (s, 3H), 2.58-2.71 (m, 2H),3.89 (s, 2H), 4.12 (s, 3H), 5.04 (br. s., 1H), 5.30-5.42 (m, 2H), 5.52(br. s., 1H), 7.59-7.71 (m, 2H), 7.94 (dd, J=8.19, 2.32 Hz, 1H), 8.15(s, 1H), 8.38 (d, J=8.31 Hz, 1H), 8.67 (s, 1H), 8.91 (s, 1H),(Exchangeable proton not observed). LCMS/HPLC: (Method-D) retentiontime: 1.70 min, [M+1]: 431.0.

Intermediate 24:4-methyl-6-(4-(oxiran-2-yl)-1H-pyrazol-1-yl)nicotinonitrile

Intermediate 24A: 4-methyl-6-(1H-pyrazol-1-yl)nicotinonitrile

Intermediate 24A was prepared (0.85 g, 60.60%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from 1H-pyrazole (0.52 g, 7.61 mmol). ¹H NMR (400 MHz, DMSO-d6)δ ppm 2.50 (s, 3H), 6.65 (s, 1H), 7.93 (s, 1H), 8.02 (s, 1H), 8.66 (s,1H), 8.85 (s, 1H). LCMS/HPLC: (Method-H) retention time: 1.63 min,[M+1]: 185.0.

Intermediate 24B: 6-(4-bromo-1H-pyrazol-1-yl)-4-methylnicotinonitrile

To a solution of Intermediate 24A (0.85 g, 4.61 mmol) in AcOH (20 mL)was added bromine (0.59 mL, 11.54 mmol) in AcOH (3 mL) drop wise. Theresulting mixture was stirred at ambient temperature for 16 h. Thereaction mixture was poured into ice water followed by the addition ofsaturated ammonium thiosulfate (10 mL). The precipitate obtained wasfiltered and dried under reduced pressure to afford Intermediate 24B(1.12 g, 92.00%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm2.60 (s, 3H), 8.02 (s, 1H), 8.08 (s, 1H), 8.88 (s, 2H). LCMS/HPLC:(Method-D) retention time: 2.89 min, [M+2]: 265.0.

Intermediate 24C: 4-methyl-6-(4-vinyl-1H-pyrazol-1-yl)nicotinonitrile

To a stirring solution of Intermediate 24B (1.12 g, 4.37 mmol) in THE(25 mL) was added tributylvinyltin (1.66 g, 5.25 mmol) and the resultingmixture was degassed with nitrogen for 15 minutes. Tripehnyphosphine(0.34 g, 1.31 mmol) followed by palladium(II) acetate (0.15 g, 0.66mmol) were added and the mixture was degassed again for 10 minutes. Theresulting reaction mixture was heated at 80° C. for 48 h then cooled toambient temperature. The reaction was filtered through Celite® and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (Redisep-40 g, 0-10% EtOAc/n-Hexane)to obtain Intermediate 24C (0.80 g, 87.00%) as an off-white solid. ¹HNMR (300 MHz, DMSO-d6) δ ppm 2.58 (s, 3H), 5.76 (d, J=17.70 Hz, 1H),5.23 (d, J=11.10 Hz, 1H), 6.61-6.71 (m, 1H), 8.02 (s, 1H), 8.17 (s, 1H),8.73 (s, 1H), 8.85 (s, 1H). LCMS/HPLC: (Method-H) retention time: 2.06min, [M+1]: 211.2.

Intermediate 24

To a stirring solution of Intermediate 24C (0.40 g, 1.90 mmol) intert-butanol (10 mL) and water (20 mL) was added NBS (0.40 g, 2.28 mmol)and the reaction mixture was heated at 40° C. for 1 h. The reactionmixture was cooled to 0° C. and NaOH (0.23 g, 5.71 mmol) in water (5 mL)was added. The reaction mixture was stirred at ambient temperature 2 h,diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine (20 mL), dried oversodium sulfate and evaporated under reduced pressure to obtainIntermediate 24 (0.30 g). LCMS: (Method-1) retention time: 1.06 min,[M+1]: 227.0. The compound was taken directly to the subsequent stepwithout further purification or characterization.

Intermediate 25-I:(R)-5-(4-((2-bromothiazol-5-yl)methyl)morpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 25A: (2-bromothiazol-5-yl)methanol

To a stirring solution of methyl 2-bromothiazole-5-carboxylate (2.00 g,9.01 mmol) in THE (40 mL) was added LiBH₄ (1.96 g, 90 mmol) and stirringwas continued at ambient temperature for 48 h. The reaction mixture wasevaporated under reduced pressure and the residue was diluted with water(50 mL) and extracted with DCM (3×75 mL). The combined organic layer waswashed with brine (50 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep-40 g, 0-35% EtOAc/n-Hexane) to obtainIntermediate 25A (0.65 g, 37.20%) as yellow solid. ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.63 (d, J=5.60 Hz, 2H), 5.67 (d, J=5.60 Hz, 1H), 7.53(s, 1H). LCMS: (Method-D) retention time: 0.68 min, [M+2]: 196.0.

Intermediate 25B: 2-bromothiazole-5-carbaldehyde

Intermediate 25B was prepared (0.38 g, 64.00%) from Intermediate 25A(0.60 g, 3.09 mmol) as a white solid, by using a similar syntheticprotocol as that of preparation of Intermediate 9 from 9E. ¹H NMR (400MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 10.00 (s, 1H). LCMS: The compound didnot ionize well.

Intermediate 25-I

Intermediate 25-I was prepared (0.35 g, 45.60%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 23-I andstarting from Intermediate 25B (0.18 g, 0.93 mmol) and intermediate 3-I(0.22 g, 0.94 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.24 (s, 3H),2.27-2.36 (m, 1H), 2.76-2.85 (m, 1H), 2.89-2.95 (m, 1H), 3.68-3.77 (m,1H), 3.78 (br. s., 2H), 3.95-4.05 (m, 1H), 4.64 (d, J=5.02 Hz, 1H),4.76-4.85 (m, 1H), 5.39 (d, J=2.01 Hz, 2H), 7.56 (s, 1H) 7.59-7.63 (m,1H), 7.64-7.70 (m, 1H). LCMS: (Method-1) retention time: 1.23 minutes,[M+2]: 411.0.

Intermediate 26-I:(R)-5-(4-(2-bromothiazole-5-carbonyl)morpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 26A: 2-bromothiazole-5-carboxylic acid

To a stirring solution of methyl 2-bromothiazole-5-carboxylate (1.50 g,6.75 mmol) in THE (10 mL), MeOH (4 mL) and water (2 mL) was added LiGH(0.81 g, 33.80 mmol) and stirring was continued at ambient temperaturefor 2 h. The reaction mixture was concentrated under reduced pressure,diluted with water (10 mL) and acidified with 2N HCl. The solidprecipitate was filtered and dried under reduced pressure to obtainIntermediate 26A (0.70 g, 49.80%) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 8.21 (s, 1H), 13.83 (br.s., 1H). LCMS: (Method-D)retention time: 0.38 min, [M+2]: 208.0.

Intermediate 26-I

To a stirring solution of Intermediate 26A (0.40 g, 1.92 mmol) andIntermediate 3-I (0.45 g, 1.92 mmol) in DCM (10 mL) was added TEA (0.80mL, 5.77 mmol) followed by Propylphosphonic anhydride (1.22 g, 3.85mmol) and stirring was continued at ambient temp for 3 h. The reactionmixture was diluted with water (20 mL) and extracted with DCM (3×30 mL).The combined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was triturated with DCM/n-Hexane to obtain Intermediate 26-I(0.80 g, 67.80%) as an off-white solid. LCMS: (Method-D) retention Time:2.06 min, [M+2]: 425.0. The compound was taken directly to thesubsequent step without further purification or characterization.

Intermediate 27: 1-(5-formylthiazol-2-yl)-1H-imidazole-4-carbonitrile

Intermediate 27 was prepared (0.12 g, 37.80%) as a light brown solid, byusing a similar synthetic protocol as that of Intermediate 11 andstarting from Intermediate 25B (0.20 g, 1.04 mmol). ¹H NMR (400 MHz,DMSO-d6) δ ppm 8.65 (s, 1H), 8.80 (s, 1H), 9.00 (s, 1H), 10.06 (s, 1H).LCMS: (Method-D) retention time: 0.96 min, [M+1]: 205.0.

Intermediate 28:6-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 28A: (1H-1,2,3-triazol-4-yl)methanol

To a solution of prop-2-yn-1-ol (2.00 g, 35.70 mmol) in a mixture of DMF(18 mL) and MeOH (0.50 mL) in a sealed tube was added TMS-N₃ (7.10 mL,53.50 mmol) and copper (I) iodide (0.34 g, 1.78 mmol) at ambienttemperature. The resulting reaction mixture was heated at 95° C. for 12h, cooled to ambient temperature, diluted with DCM (100 mL) and filteredthrough Celite®. The filtrate was evaporated under reduced pressure toobtain Intermediate 28A (3.30 g 93.00%) as a brown liquid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.55 (d, J=3.51 Hz, 2H), 5.12-5.27 (m, 1H), 7.70(br. s., 1H), 14.58-15.07 (br. s., 1H). GCMS: retention time 9.36 min,[M] 99.0. The compound was taken directly to the subsequent step withoutfurther purification.

Intermediate 28B:6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 28B was prepared (0.50 g, 20.95%) as a light brown solid,by using a similar synthetic protocol as that of Intermediate 6 andstarting from Intermediate 28A (1.00 g, 10.09 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.62 (s, 3H), 4.67 (d, J=5.52 Hz, 2H), 5.49-5.54 (m, 1H),8.12 (d, J=1.00 Hz, 1H), 8.18 (s, 1H), 8.94 (s, 1H). LCMS (Method-D):retention time 0.951 min, [M+H] 216.2.

Intermediate 28

Intermediate 28 was prepared (0.90 g, 64.20%) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 28B (1.40 g, 6.51 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.67 (s, 3H), 8.29 (s, 1H), 8.79 (s, 1H), 9.03 (s, 1H),10.21 (s, 1H). LCMS (Method-D): retention time 1.32 min, [M+H] 214.2.

Intermediate 29:2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-2H-1,2,3-triazole-4-carbaldehyde

Intermediate 29A5-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-3-methylbenzo[d]oxazol-2(3H)-one

Intermediate 29A was prepared (0.65 g, 13.78%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from Intermediate 28A (1.50 g, 15.14 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.42 (s, 3H), 4.65 (d, J=5.52 Hz, 2H), 5.43 (t, J=5.77Hz, 1H), 7.49 (d, J=8.53 Hz, 1H), 7.75 (dd, J=8.78, 2.26 Hz, 1H), 7.85(d, J=2.26 Hz, 1H), 8.02 (s, 1H). LCMS (Method-D): retention time 1.04min, [M+H] 247.2.

Intermediate 29

Intermediate 29 was prepared (0.12 g, 79.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 29A (0.15 g, 0.60 mmol). ¹H NMR (400 MHz,DMSO-d6) δ ppm 3.44 (s, 3H), 7.57 (d, J=8.78 Hz, 1H), 7.88 (dd, J=8.78,2.26 Hz, 1H), 7.99 (d, J=2.26 Hz, 1H), 8.70 (s, 1H), 10.18 (s, 1H). LCMS(Method-D): retention time 1.687 min, [M+H] 245.2.

Intermediate 30:6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Intermediate 30A: 6-azido-4-methylnicotinonitrile

To a stirring solution of 6-bromo-4-methylnicotinonitrile (2.00 g, 10.15mmol) in DMF (10 mL) was added sodium azide (1.32 g, 20.30 mmol) andstirring was continued for 12 h at ambient temperature. The reactionmixture was diluted with water (300 mL) and extracted with ethyl acetate(3×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄and evaporated under reduced pressure. The residue was purified bycolumn chromatography (Redisep-40 g, 20-35% EtOAc/n-Hexane) to obtainIntermediate 30A (0.87 g, 54.00%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.62(d, J=1.00 Hz, 3H), 8.28 (t, J=1.00 Hz, 1H), 10.21 (s, 1H). LCMS(Method-D): retention time 0.88 min, [M+H] 160.2.

Intermediate 30B:6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Intermediate 30B was prepared (0.21 g, 31.00%), by using a similarsynthetic protocol as that of Intermediate 28A and starting fromIntermediate 30A (0.50 g, 3.14 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.65 (s, 3H), 4.63 (d, J=6.53 Hz, 2H), 5.33-5.39 (m, 1H), 8.30 (d,J=1.00 Hz, 1H), 8.71 (s, 1H), 9.00 (s, 1H). LCMS (Method-D): retentiontime 0.87 min, [M+H] 216.2.

Intermediate 30

Intermediate 30 was prepared (0.13 g, 65.60%) from Intermediate 30B, byusing a similar synthetic protocol as that of preparation ofIntermediate 9 from Intermediate 9E. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.64-2.70 (m, 3H), 8.39 (s, 1H), 9.06 (s, 1H), 9.58 (s, 1H), 10.13 (s,1H). LCMS (Method-D): retention time 1.42 min, [M+H]214.2.

Intermediate 31:6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-methoxynicotinonitrile

Intermediate 31A: 6-azido-4-methoxynicotinonitrile

Intermediate 31A was prepared (1.40 g, 67.00%), by using a similarsynthetic protocol as that of Intermediate 30A and starting from6-chloro-4-methoxynicotinonitrile (2.00 g, 11.86 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.10 (s, 3H), 7.81 (s, 1H), 7.89 (s, 1H). LCMS(Method-D): retention time 0.79 min, [M+H] 176.0.

Intermediate 31B:6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-4-methoxynicotinonitrile

Intermediate 31B was prepared (0.23 g, 13.40%), by using a similarsynthetic protocol as that of Intermediate 28A and starting fromIntermediate 31A (1.30 g, 7.42 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm4.15-4.19 (m, 3H), 4.64 (s, 2H), 7.89 (s, 1H), 8.71 (s, 1H), 8.89 (s,1H), (Exchangeable proton not observed). LCMS (Method-D): retention time1.01 min, [M+H] 232.2.

Intermediate 31

Intermediate 31 was prepared (0.12 g, 60.50%) from Intermediate 31B(0.20 g, 0.86 mmol) by using a similar synthetic protocol as that ofpreparation of Intermediate 9 from Intermediate 9E. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 4.19 (s, 3H), 7.99 (s, 1H), 8.96 (s, 1H), 9.59 (s, 1H),10.14 (s, 1H). LCMS (Method-D): retention time 1.1.42 min, [M+H] 230.2.

Intermediate 32:1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-1,2,3-triazole-4-carbaldehyde

Intermediate 32A: 5-nitrobenzo[d]oxazo-2(3H)-one

To a stirred solution of 2-amino-4-nitrophenol (5.00 g, 32.40 mmol) inTHE (50 mL) was added CDI (6.84 g, 42.20 mmol) at 70° C. and stirringwas continued at ambient temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure, diluted with water (200 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (80 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 32A (5.50 g,94.00%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.49 (d,J=8.69 Hz, 1H), 7.82 (d, J=2.27 Hz, 1H), 8.02 (dd, J=8.69, 2.27 Hz, 1H).(Exchangeable proton not observed). LCMS (Method-H): retention time 0.69min, [M−H] 179.0.

Intermediate 32B: 3-methyl-5-nitrobenzo[d]oxazol-2(3H)-one

To a stirring solution of Intermediate 32A (5.00 g, 27.80 mmol) in DMSO(55 mL) was added K₂CO₃ (4.22 g, 30.50 mmol), followed by methyl iodide(5.21 mL, 83.00 mmol) and stirring was continued at ambient temperaturefor 12 h. The reaction mixture was cooled to 0° C. and diluted with icewater (150 mL). The resulting suspension was stirred at ambienttemperature for 1 h. The solid that formed was filtered, dried underreduced pressure, to obtain Intermediate 32B (4.50 g, 83.00%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.57 (d, J=8.69 Hz, 1H),8.09 (dd, J=8.69, 2.27 Hz, 1H), 8.21 (d, J=2.64 Hz, 1H), 3.43 (s, 3H).LCMS (Method-H): retention time 1.23 min, [M+H]195.2.

Intermediate 32C: 5-amino-3-methylbenzo[d]oxazol-2(3H)-one

To a solution of Intermediate 32B (1.80 g, 9.27 mmol) in acetic acid (50mL) was added 10% Pd/C (0.10 g, 0.93 mmol) and the reaction mixture wasstirred at ambient temperature under an hydrogen atmosphere for 14 h.The reaction mixture was filtered through Celite® then washed with 10%MeOH in DCM (20 mL). Filtrate was evaporated under reduced pressure toobtain Intermediate 32C (1.20 g, 80.00%). ¹H NMR (400 MHz, DMSO-d₆) δppm 3.23 (s, 3H), 5.06 (br. s., 2H), 6.28 (dd, J=8.53, 2.51 Hz, 1H),6.37 (d, J=2.01 Hz, 1H), 6.95 (d, J=8.53 Hz, 1H). LCMS (Method-D):retention time 0.59 min, [M+H] 165.2.

Intermediate 32_(D): 5-azido-3-methylbenzo[d]oxazol-2(3H)-one

To a solution of Intermediate 32C (1.50 g, 9.14 mmol) in ACN (20 mL) at0° C. was added tert-butyl nitrite (3.26 mL, 27.40 mmol) followed byazidotrimethylsilane (3.61 mL, 27.40 mmol). The resultant reactionmixture was stirred at ambient temperature for 2 h. It was diluted withwater (100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to obtain Intermediate 32_(D) (1.00 g, 57.20%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.34 (s, 3H), 6.85 (dd, J=8.53, 2.01 Hz, 1H),7.14 (d, J=2.51 Hz, 1H), 7.35 (d, J=8.53 Hz, 1H). LCMS (Method-H):retention time 2.30 min, [M+H] 191.2.

Intermediate 32E:5-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-3-methylbenzo[d]oxazol-2(3H)-one

To a stirring solution of Intermediate 32D (1.30 g, 6.84 mmol) andprop-2-yn-1-ol (0.83 g, 6.84 mmol) in a mixture of t-butanol (8 mL) andwater (8 mL) was added a freshly prepared 1 M solution of sodiumascorbate (0.55 mL, 0.55 mmol), followed by copper(II) sulfatepentahydrate (0.014 g, 0.055 mmol). The resulting reaction mixture wasstirred at ambient temperature for 8 h, diluted with DCM (200 mL), andwashed with water (100 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (Redisep-24 g, 20-35% EtOAc/n-Hexane)to obtain Intermediate 32E (1.40 g, 83.00%). ¹H NMR (300 MHz, DMSO-d₆) δppm 3.32 (s, 3H), 4.62 (d, J=5.67 Hz, 2H), 5.35 (t, J=5.67 Hz, 1H), 7.52(d, J=8.69 Hz, 1H), 7.65 (dd, J=8.50, 2.08 Hz, 1H), 7.89 (d, J=2.27 Hz,1H), 8.67 (s, 1H). LCMS (Method-H): retention time 0.62 min, [M+H]247.0.

Intermediate 32

Intermediate 32 was prepared (1.00 g, 78.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 32E (1.30 g, 5.28 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm3.41 (s, 3H), 7.58 (d, J=8.31 Hz, 1H), 7.69-7.80 (m, 1H), 7.98 (d,J=2.27 Hz, 1H), 9.55 (s, 1H), 10.13 (s, 1H). LCMS (Method-D): retentiontime 2.55 min, [M+H] 245.0.

Intermediate 33:1-(7-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 33A: 5-bromo-7-fluorobenzo[d]oxazol-2(3H)-one

A solution of 2-amino-4-bromo-6-fluorophenol (2.00 g, 9.71 mmol) and CDI(1.73 g, 10.68 mmol) in THF (20 mL) was heated at 70° C. for 2 h. Thereaction mixture was concentrated to dryness and diluted with water (30mL). The precipitated solid was filtered and dried under reducedpressure to obtain Intermediate 33A (2.00 g, 89.00%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (d, J=1.50 Hz, 1H), 7.34 (dd,J=10.00, 2.0 Hz, 1H), 7.82 (br.s, 1H). LCMS: (Method-1) retention time:1.17 min, [M+2]: 232.0.

Intermediate 33B: 5-bromo-7-fluoro-3-methylbenzo[d]oxazol-2(3H)-one

Intermediate 33B was prepared (1.90 g, 90.00%) as a black solid, byusing a similar synthetic protocol as that of Intermediate 32B andstarting from Intermediate 33A (2.00 g, 8.62 mmol).

¹H NMR (400 MHz, CDCl₃) δ 3.40 (s, 3H), 6.94 (dd, J=1.60, 0.90 Hz, 1H),7.10 (dd, J=9.3, 1.8 Hz, 1H). LCMS: (Method-1) retention time: 1.17 min,[M+2]: 248.0.

Intermediate 33

Intermediate 33 was prepared (0.06 g, 11.30%) as a brown solid, by usinga similar synthetic protocol as that of Intermediate 6 and starting fromIntermediate 33B (0.50 g, 2.03 mmol) and pyrazole-4-carbaldehyde (0.49g, 5.08 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.41 (s, 3H), 7.73 (dd,J=11.55, 2.01 Hz, 1H), 7.79 (d, J=2.01 Hz, 1H), 8.32 (s, 1H) 9.26 (s,1H), 9.93 (s, 1H). LCMS: (Method-L) retention time: 0.95 min, [M+1]:262.0.

Intermediate 34:1-(3,7-dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 34A: 4-bromo-2-methyl-6-nitrophenol

To a suspension of 4-bromo-2-methylphenol (3.00 g, 16.04 mmol) in water(25 mL) was added AcOH (1.84 mL, 32.10 mmol) followed by nitric acid(3.58 mL, 80.00 mmol) at 0° C. and the resultant reaction mixture wasstirred at ambient temperature for 30 minutes. The reaction mixture wasdiluted with water (50 mL) and extracted with ethyl acetate (2×100 mL).The combined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-40 g, 0-15%EtOAc/n-Hexane) to obtain Intermediate 34A (1.20 g, 30.00%) as a yellowsolid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.34 (s, 3H), 8.38 (dd, J=3.02,0.76 Hz, 1H), 8.59 (d, J=3.02 Hz, 1H), (Exchangeable proton notobserved). LCMS (Method-D) retention time: 2.93 min, [M+2]: 234.0

Intermediate 34B: 2-amino-4-bromo-6-methylphenol

To a solution of tin (II) chloride (5.31 g, 28.00 mmol) and conc. HCl(6.00 mL, 197.00 mmol) in MeOH (25 mL) at 0° C. was added Intermediate34A (1.30 g, 5.60 mmol). The reaction mixture was stirred at ambienttemperature for 14 h, concentrated under reduced pressure and dilutedwith water (100 mL). The mixture was basified using saturated NaHCO₃,filtered through Celite® and the filtrate was extracted with DCM (2×75ml). The combined organic extracts were dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain Intermediate34B (0.90 g, 80.00%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.15 (s, 3H), 4.83 (br. s., 2H), 6.44 (d, J=2.64 Hz, 1H), 6.61 (d,J=2.27 Hz, 1H), 8.06 (br. s., 1H). LCMS: (Method-D) retention time: 2.93min, [M+2]: 204.0 Intermediate 34C:5-bromo-7-methylbenzo[d]oxazol-2(3H)-one

Intermediate 34C was prepared (0.85 g, 84.00%) as a light brown solid,by using a similar synthetic protocol as that of Intermediate 33A andstarting from Intermediate 34B (0.90 g, 4.45 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.28 (s, 3H) 7.08 (d, J=1.51 Hz, 1H) 7.14 (s, 1H), 11.80(br.s., 1H). LCMS: (Method-D) retention time: 2.93 min, [M+2]: 230.0.

Intermediate 34D: 5-bromo-3,7-dimethylbenzo[d]oxazol-2(3H)-one

Intermediate 34D was prepared (0.90 g, 89.00%) as a light brown solid,by using a similar synthetic protocol as that of Intermediate 32B andstarting from Intermediate 34C (0.95 g, 4.17 mmol). ¹H NMR (400 MHz,CDCl₃) δ ppm 2.35 (s, 3H), 3.37 (s, 3H), 6.94 (d, J=1.51 Hz, 1H),7.08-7.10 (m, 1H). LCMS: (Method-H) retention time: 2.09 min, [M+H₂O]:260.0.

Intermediate 34

Intermediate 34 was prepared (0.08 g, 15.06%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from Intermediate 34_(D) (0.50 g, 2.07 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.39 (s, 3H), 3.38 (s, 3H), 7.58 (s, 1H), 7.70 (d, J=2.01Hz, 1H), 8.28 (s, 1H), 9.19 (s, 1H), 9.92 (s, 1H). LCMS: (Method-L)retention time: 0.94 min, [M+1]: 258.4.

Intermediate 35:1-(7-methoxy-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 35A: 4-bromo-2-methoxy-6-nitrophenol

To a stirred solution of 4-bromo-2-methoxyphenol (4.50 g, 22.16 mmol) ina mixture of diethyl ether (30 mL) and water (10 mL), was added nitricacid (1.19 mL, 26.6 mmol) over 5 minutes. The resulting reaction mixturewas stirred at ambient temperature for 30 minutes, diluted with water(50 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layer was washed with brine (50 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography (Redisep-40 g, 0-20% EtOAc/n-Hexane) to obtainIntermediate 35A (2.50 g, 45.50%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.90 (s, 3H), 7.43 (d, J=2.51 Hz, 1H), 7.60-7.64 (m, 1H),10.70 (br. s., 1H). LCMS: (Method I) retention time: 0.94 min, [M+2]:250.2.

Intermediate 35B: 2-amino-4-bromo-6-methoxyphenol

Intermediate 35B was prepared (1.50 g, 68.30%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 34B andstarting from Intermediate 35A (2.50 g, 10.08 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.73 (s, 3H), 4.79 (br. s., 2H), 6.36 (d, J=2.01 Hz, 1H),6.43-6.47 (m, 1H), 8.34 (br. s., 1H). LCMS: (Method-D) retention time:1.51 min, [M+2]: 220.0.

Intermediate 35C: 5-bromo-7-methoxybenzo[d]oxazol-2(3H)-one

Intermediate 35C was prepared (1.50 g, 82.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 33A andstarting from Intermediate 35B (1.63 g, 7.48 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.90 (s, 3H), 6.89 (d, J=1.13 Hz, 1H), 7.01 (d, J=1.51Hz, 1H), 11.80 (br. s., 1H). LCMS: (Method-D) retention time: 1.79 min,[M+2]: 246.0.

Intermediate 35_(D): 5-bromo-7-methoxy-3-methylbenzo[d]oxazol-2(3H)-one

Intermediate 35_(D) was prepared (1.40 g, 88.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 32B andstarting from Intermediate 35C (1.50 g, 6.15 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.31 (s, 3H), 3.91 (s, 3H), 7.06 (d, J=1.51 Hz, 1H), 7.19(d, J=1.13 Hz, 1H). LCMS: (Method-H) retention time 1.84 min, [M+H₂O]:275.0.

Intermediate 35

Intermediate 35 was prepared (0.24 g, 45.30%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from Intermediate 35_(D) (0.50 g, 1.94 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.34 (s, 3H), 4.00 (s, 3H), 7.42 (d, J=1.89 Hz, 1H), 7.51(d, J=1.89 Hz, 1H), 8.30 (s, 1H), 9.28 (s, 1H), 9.93 (s, 1H). LCMS:(Method-L) retention time: 0.90 min, [M+1]: 274.1.

Intermediate 36:6-(4-formyl-3-methyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 36 was prepared (0.21 g, 25.60%) as a beige solid, by usinga similar synthetic protocol as that of Intermediate 6 and starting from3-methyl-1H-pyrazole-4-carbaldehyde (0.40 g, 3.63 mmol) and6-bromo-4-methylnicotinonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.52(s, 3H), 2.6 (s, 3H), 8.01 (s, 1H), 8.90 (s, 1H), 9.28 (s, 1H), 10.00(s, 1H). LCMS: (method-H) retention time 1.85 min, [M+H] 227.0.

Intermediate 37:6-(3-formyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 37 was prepared (0.27 g, 30.50%), by using a similarsynthetic protocol as that of Intermediate 6 and starting from1H-pyrazole-3-carbaldehyde (0.40 g, 4.16 mmol) and6-bromo-4-methylnicotinonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.50-2.68 (s, 3H), 7.20-7.22 (s, 1H), 8.03 (s, 1H), 8.09-8.17 (s, 1H),8.95-8.99 (s, 1H), 10.48 (s, 1H). LCMS: (method-1) retention time 1.00min, [M+H] 213.0.

Intermediate 38-I:5-((2R,6R)-6-(hydroxymethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 38A: methyl6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrazine-2-carboxylate

Intermediate 38A was prepared (6.20 g, 75.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 2B (8.74 g, 31.90 mmol) and6-chloropyrazine-2-carboxylate (5.00 g, 29.00 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.34 (s, 3H), 3.96 (s, 3H), 5.52 (s, 2H), 7.76 (d, J=8.03Hz, 1H), 7.85 (d, J=7.53 Hz, 1H), 9.16 (s, 1H), 9.26 (s, 1H). LCMS(Method-J): retention time 1.15 min, [M+H] 285.2.

Intermediate 38B: methyl6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-2-carboxylate

Intermediate 38B was prepared (4.00 g, 97.00%), by using a similarsynthetic protocol as that of Intermediate 2-I and starting fromIntermediate 38A (4.00 g, 14.07 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.25-2.32 (m, 4H), 2.54-2.62 (m, 1H), 2.82 (d, J=12.55 Hz, 1H), 3.10 (d,J=12.05 Hz, 1H), 3.54-3.60 (m, 1H), 3.70 (s, 3H), 4.06 (d, J=8.03 Hz,1H), 5.32-5.43 (m, 2H), 7.62-7.71 (m, 1H), 7.76-7.83 (m, 1H), (2Exchangeable protons not observed). LCMS (Method-1): retention time 0.49min, [M+H] 291.5.

Intermediate 38C: 1-(tert-butyl) 3-methyl5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1,3-dicarboxylate

Intermediate 38C was prepared (4.50 g, 95.00%), by using a similarsynthetic protocol as that of Intermediate 18B-II and starting fromIntermediate 38B (3.50 g, 12.06 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.31-1.51 (m, 9H), 2.26-2.39 (m, 3H), 2.74-2.95 (m, 1H), 3.06 (br. s.,1H), 3.58 (d, J=8.03 Hz, 1H), 3.72 (s, 3H), 3.82-3.94 (m, 1H), 4.03 (d,J=8.53 Hz, 1H), 4.13-4.28 (m, 1H), 5.38-5.46 (m, 2H), 7.64-7.76 (m, 1H),7.82 (d, J=7.53 Hz, 1H), (1 Exchangeable proton not observed). LCMS(Method-1): retention time 1.17 min, [M+H] 391.6.

Intermediate 38D-I, II, III and IV: tert-butyl3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a solution of Intermediate 38C (6.20 g, 11.12 mmol) in a mixture ofTHF (50 mL) and EtOH (50 mL) was added LiCl (0.94 g, 22.23 mmol) andNaBH₄ (0.84 g, 22.23 mmol) under a nitrogen atmosphere and the reactionmixture was stirred at ambient temperature for 14 h. The reactionmixture was quenched with 10% aqueous solution of sodium bicarbonate(150 mL) and extracted with ethyl acetate (3×150 mL). The combinedorganic layers were washed with brine (100 mL), dried over anhydroussodium sulfate and evaporated under reduced pressure. The residue waspurified by preparative HPLC [Sunfire OBD (250×30 ID) 5 micron; SolventA: 10 mM Ammonium acetate in water, Solvent B: Acetonitrile, Gradient:30-100% B over 16 min, Flow: 25 mL/min] to obtain diastereomer-I and II.The diastereomer-I was separated into two individual enantiomers bysupercritical fluid chromatography (SFC) [Chiralpak ADH (250×4.6 mm) 5micron; 0.2% NH₄OH in MeOH, Flow: 3.0 mL/min. Temperature: 30° C., UV:210 nm]. First eluted compound (retention time 2.67 min), designated asIntermediate 38D-I, was obtained (1.10 g, 27.30%) as white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H), 2.32 (s, 3H), 2.78 (dd, J=10.79,3.26 Hz, 1H), 3.37-3.43 (m, 3H), 3.79-4.11 (m, 4H), 4.73 (br. s., 1H),5.41 (s, 2H), 7.69 (d, J=8.03 Hz, 1H), 7.81 (d, J=8.03 Hz, 1H), (1Exchangeable proton not observed). LCMS (Method-1): retention time 0.97min, [M+H] 363.2. Chiral purity (Method-XII): retention time 2.69 min,100% ee. SOR: [α]²⁵ _(D)=−26.00 (c 0.1, MeOH).

Second eluted compound (retention time 3.72 min), designated asIntermediate 38D-II, was obtained (1.10 g, 27.30%) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H), 2.32 (s, 3H), 2.78 (dq,J=13.62, 2.99 Hz, 1H), 3.38-3.44 (m, 3H), 3.82-4.12 (m, 4H), 4.74 (br.s., 1H), 5.41 (s, 2H), 7.69 (d, J=8.03 Hz, 1H), 7.81 (d, J=8.03 Hz, 1H),(1 Exchangeable proton not observed). LCMS (Method-1): retention time0.97 min, [M+H] 363.2. Chiral purity (Method-XII): retention time 3.81min, 100% ee.

The diastereomer-II was separated into two individual enantiomers by SFC[Luxcellulose-2 (250×21.5 mm) 5 micron; 0.2% NH₄OH in MeOH+ACN (1:1)Flow: 3.0 g/min. Temperature: 30° C., UV: 235 nm]. First eluted compound(retention time 6.64 min), designated as Intermediate 38D-III, wasobtained (0.25 g, 6.21%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.41 (s, 9H), 2.26-2.37 (m, 3H), 2.96 (br. s., 1H), 3.39(br. s., 2H), 3.57 (d, J=10.54 Hz, 2H), 3.70-3.92 (m, 3H), 4.67 (br. s.,1H), 5.40 (s, 2H), 7.68 (d, J=8.03 Hz, 1H), 7.84 (d, J=8.03 Hz, 1H), (1Exchangeable proton not observed). LCMS (Method-1): retention time 0.92min, [M+H] 363.2. Chiral purity (Method-XIX): retention time 6.69 min,100% ee. SOR: [α]²⁵ _(D)=+26.00 (c 0.1, MeOH). Second eluted compound(retention time 8.49 min), designated as Intermediate 38D-IV, wasobtained as a white solid (0.25 g, 6.21%). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.41 (s, 9H), 2.28-2.36 (m, 3H), 2.96 (br. s., 1H), 3.35-3.46 (m,2H), 3.58 (br. s., 3H), 3.75 (d, J=14.05 Hz, 1H), 4.67 (t, J=5.27 Hz,2H), 5.40 (s, 2H), 7.68 (d, J=8.03 Hz, 1H), 7.84 (d, J=8.03 Hz, 1H), (1Exchangeable proton not observed). LCMS (Method-1): retention time 0.92min, [M+H] 363.2. Chiral purity (Method-XIX): retention time 8.62 min,100% ee.

Intermediate 38-I

To a solution of Intermediate 38D-I (1.50 g, 4.14 mmol) in MeOH (50 mL)was added 4 N HCl in dioxane (20 mL, 80 mmol). The reaction mixture wasstirred at ambient temperature for 1 h and was concentrated to dryness.The residue was diluted with MeOH (100 mL), cooled to 0° C. and ammoniawas purged through it for 5 min. The resulting clear solution wasconcentrated under reduced pressure to obtain Intermediate 38-I (1.00 g,92.00%). The compound was taken directly to the subsequent step withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3H),2.59-2.77 (m, 2H), 2.82-2.95 (m, 2H), 3.38-3.44 (m, 2H), 3.73 (br. s.,1H), 3.87 (d, J=11.04 Hz, 1H), 4.04-4.23 (m, 1H), 5.41 (s, 2H), 7.70 (d,J=7.53 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H), (2 Exchangeable protons notobserved). LCMS (Method-1): retention time 0.40 min, [M+H]263.2. Todetermine stereochemistry of Intermediate 38-I,5-((2R,6R)-4-(4-bromobenzoyl)-6-(hydroxymethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-onewas prepared according to literature procedure (US2002/156081A1, 2002),and absolute configuration was determined by single-crystal X-raydiffraction method.

Intermediate 39-I:5-(6-(hydroxymethyl-d2)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 39A-I, II, III and IV: tert-butyl3-(hydroxymethyl-d2)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

Intermediate 39A-I, II, III and IV was prepared, by using a similarsynthetic protocol as that of Intermediate 38A-I, II, III and IV andstarting from Intermediate 38C (1.40 gm, 2.51 mmol and NaBD₄ (0.21 g,5.02 mmol). The crude residue was purified by preparative HPLC [SunfireOBD (250×30 ID) 5 micron; Solvent A: 10 mM Ammonium acetate in water,Solvent B: Acetonitrile, Gradient: 30-100% B over 16 min, Flow: 25mL/min] to obtain diastereomer-I and II. The diastereomer-I wasseparated into two individual enantiomers by SFC [Chiralpak ADH (250×4.6mm) 5 micron; 0.2% NH₄OH in MeOH, Flow: 3.0 g/min. Temperature: 30° C.,UV: 210 nm]. First eluted compound (retention time 2.67 min), designatedas Intermediate 39A-I, was obtained (0.20 g, 21.80%) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.43 (s, 9H), 2.33 (s, 3H), 2.39-2.47 (m,2H), 2.65-2.81 (m, 2H), 3.86-4.14 (m, 3H), 4.72 (s, 1H), 5.42 (s, 2H),7.70 (d, J=8.03 Hz, 1H), 7.82 (d, J=8.03 Hz, 1H). LCMS (Method-1):retention time 0.97 min, [M+H] 365.3. Chiral purity (Method-XII):retention time 2.27 min, 100% ee. Second eluted compound (retention time3.72 min), designated as Intermediate 39A-II, was obtained (0.20 g,21.80%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43 (s, 9H),2.33 (s, 3H), 2.38-2.47 (m, 2H), 2.67-2.83 (m, 2H), 3.84-4.08 (m, 3H),4.69-4.75 (m, 1H), 5.42 (s, 2H), 7.70 (d, J=8.03 Hz, 1H), 7.82 (d,J=8.03 Hz, 1H). LCMS (Method-1): retention time 0.97 min, [M+H] 365.3.Chiral purity (Method-XII): retention time 2.97 min, 95.40% ee.

The diastereomer-II was separated into two individual enantiomers by SFC[Luxcellulose-2 (250×21.5 mm) 5 micron; 0.2% NH₄OH in MeOH+ACN (1:1)Flow: 70.0 g/min. Temperature: 30° C., UV: 235 nm]. First elutedcompound (retention time 6.59 min), designated as Intermediate 39A-III,was obtained (0.05 g, 5.47%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.42 (s, 9H), 2.28-2.36 (m, 3H), 2.64-2.74 (m, 2H), 2.87-3.02 (m,1H), 3.18 (s, 2H), 3.70-3.94 (m, 2H), 4.26 (d, J=9.54 Hz, 1H), 5.42 (s,2H), 7.69 (d, J=8.03 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H). LCMS (Method-1):retention time 0.93 min, [M+H] 365.3. Chiral purity (Method-XIX):retention time 6.56 min, 100% ee. Second eluted compound (retention time8.32 min), designated as Intermediate 39A-IV, was obtained (0.05 g,5.47%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H),2.28-2.37 (m, 3H), 2.66-2.72 (m, 2H), 2.87-3.02 (m, 1H), 3.18 (s, 2H),3.70-3.94 (m, 2H), 4.26 (d, J=10.54 Hz, 1H), 5.42 (s, 2H), 7.69 (d,J=8.03 Hz, 1H), 7.85 (d, J=7.53 Hz, 1H). LCMS (Method-I): retention time0.93 min, [M+H] 365.3. Chiral purity (Method-XX): retention time 8.32min, 98% ee.

Intermediate 39-I

Intermediate 39-I was prepared (0.13 g, 93.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 38-I andstarting from Intermediate 39A-I (0.20 g, 0.55 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.34 (s, 3H), 2.57-2.69 (m, 2H), 3.17 (d, J=10.54 Hz,1H), 3.21-3.31 (m, 2H), 4.59 (d, J=9.54 Hz, 1H), 4.96 (br. s., 1H),5.33-5.48 (m, 2H), 7.70 (d, J=8.03 Hz, 1H), 7.80 (d, J=8.03 Hz, 1H), (2Exchangeable proton not observed). LCMS (Method-1): retention time 0.39min, [M+H] 265.2.

Intermediate 40-I:5-(6,6-dimethylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 40A: 5-(2-bromoacetyl)-4-methylisobenzofuran-1(3H)-one

Synthesized according to similar literature procedure (WO2010/129379,A1, 2010)

Intermediate 40B:2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoacetaldehyde

To a solution of Intermediate 40A (2.65 g, 7.88 mmol) in a mixture ofDMSO (15 mL) and water (0.142 mL) was added 48% HBr in water (0.018 mL,0.158 mmol) and the reaction mixture was heated at 80° C. for 5 h. Thereaction mixture was cooled to room temperature, diluted with water (50mL), basified by 10% aqueous solution of sodium bicarbonate (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 40B (1.00 g,43.50%) as an off-white solid. The compound was taken directly to thesubsequent step without further purification. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.29 (s, 3H), 5.54 (br. s., 2H), 7.20 (dd, J=8.07, 0.98 Hz, 1H),7.74-7.88 (m, 1H), 7.95 (d, J=8.31 Hz, 1H). LCMS (Method-1): retentiontime 0.82 min, [M−H] 203.0.

Intermediate 40C: tert-butyl3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a solution of Intermediate 40B (0.95 g, 3.72 mmol) in a mixture ofTHE (24 mL) and MeOH (6 mL) was added 2-methylpropane-1,2-diamine (0.33g, 3.72 mmol) and the reaction mixture was stirred at ambienttemperature for 1 h. NaBH₄ (0.28 g, 7.44 mmol) was added and theresulting mixture was stirred for 30 min. TEA (1.556 mL, 11.17 mmol)followed by BOC₂O (0.864 mL, 3.72 mmol) were added and the reactionmixture was stirred at ambient temperature for 14 h, diluted with water(100 mL) and extracted with DCM (3×50 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep—40 g, 50% EtOAc/n-hexane) to obtain racemate(1.10 g). The racemate was separated into two individual enantiomers bySFC [Chiralpak ADH (250×21.5 mm) 5 micron; 0.2% NH₄OH in MeOH+ACN (1:1),Flow; 3.0 g/min. Temperature: 30° C., UV: 235 nm]. First eluted compound(retention time 3.02 min), designated as Intermediate 40C-I, wasobtained (0.40 g, 29.80%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.13 (d, J=16.56 Hz, 6H), 1.37-1.48 (m, 9H), 2.34 (s, 3H), 2.64-2.77(m, 2H), 3.71 (br. s., 1H), 3.97 (br. s., 1H), 4.26 (d, J=8.03 Hz, 1H),5.33-5.48 (m, 2H), 7.70 (d, J=8.03 Hz, 1H), 7.83 (d, J=8.03 Hz, 1H), (1Exchangeable proton not observed). LCMS (Method-I): retention time 1.61min, [M+H]361.4. Chiral purity (Method-XII): retention time 3.04 min,100% ee. Second eluted compound (retention time 4.42 min), designated asIntermediate 40C-II, was obtained (0.40 g, 29.80%) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.13 (d, J=16.56 Hz, 6H), 1.44 (s, 9H),2.30-2.40 (m, 3H), 2.68 (d, J=2.01 Hz, 2H), 3.73 (br. s., 1H), 3.94 (s,1H), 4.26 (d, J=9.54 Hz, 1H), 5.42 (s, 2H), 7.70 (d, J=8.03 Hz, 1H),7.83 (d, J=8.03 Hz, 1H) (1 Exchangeable proton not observed). LCMS(Method-I): retention time 1.61 min, [M+H] 361.4. Chiral purity(Method-XI): retention time 4.44 min, 100% ee.

Intermediate 40-I

Intermediate 40-I was prepared (0.26 g, 90.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 38-I andstarting from Intermediate 40C-I (0.40 g, 1.11 mmol). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.06 (s, 3H), 1.28 (s, 3H), 2.42 (s, 3H), 2.46 (dd,J=12.01, 10.51 Hz, 1H), 2.54-2.60 (m, 1H), 2.64-2.71 (m, 1H), 2.95 (dt,J=12.01, 1.50 Hz, 1H), 4.31 (dd, J=10.51, 2.75 Hz, 1H), 5.12-5.20 (m,2H), 7.63-7.70 (m, 1H), 7.71-7.78 (m, 1H), (2 Exchangeable protons notobserved). LCMS (Method-1): retention time 0.47 min, [M−H] 261.3.

Intermediate 41:6-(4-formyl-1H-pyrazol-1-yl)-2-methoxynicotinonitrile

Intermediate 41A: 6-chloro-2-methoxynicotinonitrile and Intermediate41B: 2-chloro-6-methoxynicotinonitrile

To a solution of 2,6-dichloronicotinonitrile (0.50 g, 2.89 mmol) in MeOH(10 mL) was added sodium methoxide (0.62 g, 2.89 mmol) at ambienttemperature and the resulting mixture was stirred at 60° C. for 12 h.The reaction mixture was cooled to ambient temperature, concentrated todryness under reduced pressure. The residue was diluted with water (50mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine (30 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby preparative HPLC [Xbridge Phenyl (250×21.2 ID) 5 micron; Solvent A:0.1% TFA in water, Solvent B: Acetonitrile, Gradient: 0-100% B over 20min, Flow: 20 mL/min, UV 220 nm]. First eluted compound (retention time15.34 min), designated as Intermediate 41A, was obtained (0.10 g,19.70%) as white solid, ¹H NMR (400 MHz, CDCl₃) δ ppm 4.08 (s, 3H), 7.02(d, J=7.83 Hz, 1H), 7.82 (d, J=7.83 Hz, 1H). LCMS (Method-D): retentiontime 1.94 min, [M+1H] 169.2. Second eluted compound (retention time16.74 min), designated as Intermediate 41B, was obtained (0.04 g, 1.64%)as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H),7.07 (s, 1H), 8.29 (d, J=8.53 Hz, 1H). LCMS (Method-D): retention time1.89 min, [M+1H] 169.2. Structure of Intermediate 41A and 41B wasdetermined by single-crystal X-ray diffraction method.

Intermediate 41

Intermediate 41 was prepared (0.15 g, 62.20%) as pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 11 andstarting from Intermediate 41A (0.16 g, 0.98 mmol). ¹H NMR (400 MHz,DMSO-d6) δ ppm 4.15 (s, 3H), 7.65-7.67 (d, J=6 Hz, 1H), 8.38 (s, 1H),8.45-8.47 (d, J=6 Hz, 1H), 9.44 (s, 1H), 9.99 (s, 1H). LCMS: Thecompound did not ionize well.

Intermediate 42:2-(4-formyl-1H-imidazol-1-yl)-4,6-dimethylpyrimidine-5-carbonitrile

Intermediate 42A: 5-bromo-4,6-dimethylpyrimidin-2-amine

Synthesized according to literature procedures (WO2011/103536 A1, 2011).

Intermediate 42B: 2-amino-4,6-dimethylpyrimidine-5-carbonitrile

To a solution of Intermediate 42A (6.00 g, 29.70 mmol) in DMF (50 mL)was added copper (I) cyanide (3.99 g, 44.55 mmol) and the resultingmixture was heated at 180° C. for 16 h. The reaction mixture was cooledto ambient temperature, diluted with water (50 mL) and ethyl aceate (100mL). The resulting mixture was filtered through Celite® and the filtratewas concentrated under reduced pressure to obtain Intermediate 42B (3.00g, 54.00%). The compound was taken directly to the subsequent stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32-2.41(m, 6H), 7.533 (s, 2H). LCMS (Method-D): retention time 0.72 min, [M+H]149.1.

Intermediate 42C: 2-bromo-4,6-dimethylpyrimidine-5-carbonitrile

To a solution of isoamyl nitrite (4.91 mL, 36.4 mmol) in acetonitrile(50 mL) at 0° C. was added copper(II)bromide (8.14 g, 36.40 mmol). Theresulting reaction mixture was stirred at ambient temperature for 10minutes and Intermediate 42B (2.70 g, 18.22 mmol) in acetonitrile (10mL) was added and the stirring was continued for 3 h. The reactionmixture was diluted with water (30 mL) and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine (30 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep—40g, 10-20% EtOAc/n-hexane) to obtain Intermediate 42C (0.90 g, 23.90%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.50-2.63 (m, 6H). LCMS (Method-D):retention time 1.692 min, [M+H] 211.9.

Intermediate 42

To a solution of 1H-imidazole-4-carbaldehyde (0.50 g, 5.20 mmol) andIntermediate 42C (1.10 g, 5.20 mmol) in DMF (15 mL) was addedtriethylamine (2.18 mL, 15.61 mmol). The resulting reaction mixture wasstirred at ambient temperature for 1.5 h. The reaction mixture wasconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography (Redisep-24 g, 40% EtOAc/n-hexane) to obtainIntermediate 42 (0.25 g, 21.14%) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.89-2.73 (s, 6H), 8.80 (s, 2H), 9.88 (s, 1H). LCMS(method-D): retention time 1.41 min, [M+H] 228.2.

Intermediate 43:2-(4-formyl-1H-pyrazol-1-yl)-4-methylpyrimidine-5-carbonitrile

Intermediate 43A: (E)-2-((dimethylamino)methylene)-3-oxobutanenitrile

To a solution of 3-oxobutanenitrile (10.00 g, 120.00 mmol) in DMF (30mL) was added DMF-DMA (19.34 mL, 144.00 mmol) and the resulting mixturewas stirred at 80° C. for 16 h. The reaction was cooled to ambienttemperature, concentrated to dryness under reduced pressure, dilutedwith n-hexane (200 mL). The solid precipitate was filtered and driedunder vacuum to obtain Intermediate 43A (13.00 g, 78.00%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.17 (s, 3H), 3.25 (s, 3H), 3.29 (s, 3H), 7.83 (s,1H). LCMS (Method-L): retention time 0.54 min, [M+H] 139.2.

Intermediate 43B: 2-amino-4-methylpyrimidine-5-carbonitrile

To a stirred solution of Intermediate 43A (12.00 g, 87.00 mmol) in EtOH(25 mL) was added guanidine carbonate (31.30 g, 174.00 mmol) and sodiumacetate (21.37 g, 261.00 mmol) and the reaction was stirred at 80° C.for 5 h. The reaction mixture was cooled to ambient temperature,concentrated to dryness and diluted with n-hexane (200 mL). The solidprecipitate was filtered, washed with EtOH (30 mL) and dried undervacuum to obtain Intermediate 43B (9.50 g, 82.00%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.38 (s, 3H), 7.62 (s, 2H), 8.53 (s, 1H). LCMS(Method-L): retention time 0.54 min, [M+H] 135.1.

Intermediate 43C: 2-bromo-4-methylpyrimidine-5-carbonitrile

To a solution of Intermediate 43B (5.00 g, 37.30 mmol) in a mixture ofTHE (75 mL) and DMF (15 mL) was added copper(II)bromide (16.65 g, 74.50mmol), isoamyl nitrite (7.53 ml, 55.9 mmol) at ambient temperature andthe reaction mixture was refluxed for 1 h. The reaction mixture wascooled to ambient temperature, concentrated to dryness under reducedpressure, diluted with DCM (200 mL), solid precipitate was filtered andwashed with THF (200 mL). The combined organic filtrate were washed with10% aqueous solution of sodium bicarbonate (150 mL) and brine (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-120g, 0-15% EtOAc/n-Hexane) to obtain Intermediate 43C (0.75 g, 10.00%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.65 (s, 3H), 9.08 (s, 1H). LCMS(Method-L): retention time 0.92 min, [M+2H] 199.1.

Intermediate 43

Intermediate 43 was prepared (0.04 g, 14.00%), by using a similarsynthetic protocol as that of Intermediate 15C and starting fromIntermediate 43C (0.30 g, 1.56 mmol) and 1H-pyrazole-4-carbaldehyde(0.18 g, 1.89 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.66 (s, 3H), 8.37(s, 1H), 9.31 (s, 1H), 9.44 (s, 1H), 10.00 (s, 1H). LCMS (Method-L):retention time 0.74 min, [M+H] 214.1.

Intermediate44:2-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methylpyrimidine-5-carbonitrile

Intermediate 44A:2-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methylpyrimidine-5-carbonitrile

To a solution of (2H-1,2,3-triazol-4-yl)methanol (0.75 g, 0.76 mmol) inDMF (10 mL) was added K₂CO₃ (1.08 g, 7.81 mmol), Intermediate 43C (0.10g, 0.50 mmol) and the reaction mixture was stirred at ambienttemperature for 1 h. The reaction mixture was concentrated to drynessunder reduced pressure, diluted with water (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were washed withbrine (30 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure to obtain Intermediate 44A (0.02 g, 18.00%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.75 (s, 3H), 4.68 (s, 2H), 8.22 (s, 1H), 9.37(s, 1H), (1 Exchangeable proton not observed). LCMS (Method-O):retention time 0.74 min, [M−H] 215.1.

Intermediate 44

Intermediate 44 was prepared (0.19 g, 77.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 44A (0.25 g, 1.16 mmol) and dess-martinperiodinane (0.61 g,1.44 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.80 (s, 3H), 8.80 (s, 1H),9.42 (s, 1H), 10.23 (s, 1H). LCMS (Method-O): retention time 0.59 min,[M+H] 215.1.

Intermediate 45:2-(4-formyl-1H-pyrazol-1-yl)-4-methoxypyrimidine-5-carbonitrile

Intermediate 45A: 2-chloro-4-methoxypyrimidine-5-carbonitrile

Synthesized according to literature procedures (US2015/291629 A1, 2015).

Intermediate 45

Intermediate 45 was prepared (0.15 g, 55.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 11 andstarting from Intermediate 45A (0.20 g, 1.18 mmol) and1H-pyrazole-4-carbaldehyde (0.17 g, 1.77 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.20 (s, 3H), 8.38 (s, 1H), 9.18 (s, 1H), 9.48 (s, 1H),10.00 (s, 1H). LCMS (Method-O): retention time 0.75 min, [M+H] 230.1.

Intermediate46:2-(4-formyl-1H-imidazol-1-yl)-4-methoxypyrimidine-5-carbonitrile

Intermediate 46 was prepared (0.75 g, 55.50%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 11 andstarting from Intermediate 45A (1.00 g, 5.90 mmol)) and1H-imidazole-4-carbaldehyde (1.13 g, 11.79 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.23 (s, 3H), 8.84 (s, 1H), 8.87 (s, 1H), 9.19 (s, 1H),9.88 (s, 1H). LCMS (Method-1): retention time 0.80 min, [M+H] 230.2.

Intermediate 47: 6-(4-formyl-1H-imidazol-1-yl)-4-methylnicotinonitrile

Intermediate 47 was prepared (0.10 g, 9.28%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 15C andstarting from 6-bromo-4-methylnicotinonitrile (1.0 g, 5.08 mmol) and1H-imidazole-4-carbaldehyde (0.61 g, 6.34 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.59 (s, 3H), 8.17 (s, 1H), 8.79 (s, 1H), 8.84 (s, 1H),8.95 (s, 1H), 9.86 (s, 1H). LCMS (Method-L): retention time 0.73 min,[M+H] 213.1.

Intermediate 48: 4-(4-formyl-1H-imidazol-1-yl)-2-methoxybenzonitrile

To a stirred solution of 1H-imidazole-4-carbaldehyde (1.00 g, 10.41mmol) in dioxane (5 mL) was added 4-bromo-2-methoxybenzonitrile (2.20 g,10.41 mmol), N,N-Dimethylglycine (1.073 g, 10.41 mmol) and Cs₂CO₃ (3.39g, 10.41 mmol) followed by copper(I)iodide (1.98 g, 10.41 mmol). Theresulting reaction mixture was heated at 110° C. for 16 h in a sealedtube. The reaction mixture was cooled to ambient temperature,concentrated to dryness under vacuum, diluted with water (40 mL) andextracted with DCM (2×100 mL). The combined organic layers were washedwith brine (50 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain Intermediate 48 (0.80 g, 33.80%) asbrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.04 (s, 3H), 7.56 (dd,J=8.35, 1.95 Hz, 1H), 7.66 (d, J=1.44 Hz, 1H), 7.97 (d, J=8.41 Hz, 1H),8.67-8.72 (m, 1H), 8.85-8.89 (m, 1H), 9.84-9.87 (m, 1H). LCMS(Method-O): retention time 0.76 min, [M+H] 228.1.

Intermediate 49: 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 49 was prepared (0.50 g, 49.50%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 48 andstarting from 4-bromo-2-methylpyridine (1.00 g, 5.81 mmol) and1H-pyrazole-4-carbaldehyde (0.84 g, 8.72 mmol). The compound was takendirectly to the subsequent step without further purification orcharacterization. LCMS (Method-O): retention time 0.69 min, [M+H] 188.2.

Intermediate 50:2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidine-5-carbaldehyde

Intermediate 50A: 4,5-dimethyl-1H-imidazole

Synthesized according to literature procedures (Angewandte Chemie, 49,(2010), 5322-5326).

Intermediate 50

To a solution of 4,5-dimethyl-1H-imidazole (0.15 g, 1.60 mmol) inacetonitrile (10 mL) was added K₂CO₃ (0.44 g, 3.21 mmol),2-bromopyrimidine-5-carbaldehyde (0.20 g, 1.07 mmol) and the resultingmixture was stirred at ambient temperature for 1.5 h. The reactionmixture was diluted with ethyl acetate (50 mL) and filtered throughCelite®. The filtrate was evaporated under reduced pressure. The residuewas purified by column chromatography (Redisep-24 g, 40% EtOAc/n-hexane)to obtain Intermediate 50 (0.18 g, 86.00%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.13 (d, J=0.49 Hz, 3H), 2.16 (s, 3H), 8.47 (s, 1H),9.27 (s, 2H), 10.11 (s, 1H). LCMS: The compound did not ionize well.

Intermediate 51-I:4-methyl-5-((2R,6S)-6-methylpiperazin-2-yl)isobenzofuran-1(3H)-one4-methyl-5-(6-methylpyrazin-2-yl)isobenzofuran-1(3H)-oneand Intermediate 51-I:4-methyl-5-((2S,6R)-6-methylpiperazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 51A:4-methyl-5-(6-methylpyrazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 51A was prepared (14.00 g, 80.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 2B (20.00 g, 7.3.00 mmol) and2-chloro-6-methylpyrazine (9.38 g, 73.0 mmol). ¹H NMR (400 MHz, DMSO-d6)δ ppm 2.23 (s, 3H), 2.59 (s, 3H) 5.50 (s, 2H), 7.69 (d, J=7.83 Hz, 1H),7.81 (d, J=7.83 Hz, 1H), 8.62 (s, 1H), 8.69 (s, 1H). LCMS (Method-D):retention time 1.41 min, [M+H] 241.2.

Intermediate 51-I and 51-II

Intermediate 51-I and 51-II was prepared by using a similar syntheticprotocol as that of Intermediate 2-I and 2-II and starting fromIntermediate 51A (10.00 g, 41.6 mmol). The racemate was separated intotwo individual enantiomers by SFC [Chiralpak IC (250×4.6 mm) 5 micron;0.2% NH₄OH in MeOH+ACN (1:1), Flow: 1.2 mL/min. Temperature: 30° C., UV:235 nm]. First eluted compound (retention time 4.83 min), designated asIntermediate 51-I, was obtained (3.50 g, 41.00%) as brown solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.96 (d, J=6.02 Hz, 3H) 2.14-2.22 (m, 2H) 2.29(s, 3H) 2.74-2.84 (m, 3H) 4.02 (dd, J=10.04, 2.51 Hz, 1H) 5.38 (s, 2H)7.65 (d, J=8.03 Hz, 1H) 7.81 (d, J=8.03 Hz, 1H), (2 Exchangeable protonnot observed). LCMS (Method-D): retention time 0.636 min, [M+H] 247.2.Chiral purity (Method-XXVII): retention time 4.86 min, 99.30% ee. SOR:[α]²⁵ _(D)=−38.00 (c 0.10, MeOH). To determine stereochemistry ofIntermediate 51-I,5-((2R,6S)-4-(3,5-dibromobenzoyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-onewas prepared according to literature procedure (WO2011/012896, 2011),and absolute configuration was determined by single-crystal X-raydiffraction method. Second eluted compound (retention time 6.12 min),designated as Intermediate 51-II, was obtained (3.10 g, 36.00%) as brownsolid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J=6.02 Hz, 3H),2.12-2.26 (m, 2H), 2.29 (s, 3H), 2.74-2.84 (m, 3H), 4.02 (dd, J=10.04,2.51 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.81 (d, J=8.03 Hz,1H), (2 Exchangeable proton not observed). LCMS (Method-D): retentiontime 0.548 min, [M+H] 247.2. Chiral purity (Method-XXVII): retentiontime 5.96 min, 96.00% ee. SOR: [α]²⁵ _(D)=+32.00 (c 0.10, MeOH).

Intermediate 52-I:5-((3R,4R)-4-hydroxypiperidin-3-yl)-4-methylisobenzofuran-1(3H)-onehydrochloride

Intermediate 52A-I, II, III and IV: tert-butyl4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a solution of Intermediate 4A (4.00 g, 11.58 mmol) in MeOH (100 mL)was added NaBH₄ (1.46 g, 23.16 mmol) and the reaction mixture wasstirred at ambient temperature for 2 h. The reaction mixture wasconcentrated to dryness under reduced pressure and diluted with water(100 mL). The solid precipitate was filtered and dried under vacuum toobtain diastereomer-I (2.7 gm). Filtrate was extracted with 10% MeOH inDCM (3×50 mL). The combined organic layers were washed with brine (30mL), dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain diastereomer-II (0.8 g). The diastereomer-I wasseparated into two individual enantiomers by SFC [Lux cellulose-2(250×4.6 mm) 5 micron; 0.2% NH₄OH in MeOH, Flow: 1.2 mL/min.Temperature: 30° C., UV: 240 nm]. First eluted compound (retention time3.98 min), designated as Intermediate 52A-I, was obtained (1.20 g,30.00%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s,9H), 1.89-1.98 (m, 1H), 2.29 (s, 3H), 2.82 (d, J=9.54 Hz, 3H), 3.17 (d,J=4.02 Hz, 1H), 3.78 (br. s., 1H), 3.95 (br. s., 2H), 4.70 (br. s., 1H),5.40 (s, 2H), 7.55 (d, J=8.03 Hz, 1H), 7.66 (d, J=8.03 Hz, 1H). Chiralpurity (Method-XXVIII): retention time 3.98 min, 100% ee. SOR: [α]²⁵_(D)=−38.00 (c 0.1, MeOH). LCMS: The compound did not ionize well.Second eluted compound (retention time 5.85 min), designated asIntermediate 52A-II, was obtained (1.30 g, 32.30%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H), 1.89-1.98 (m, 1H),2.29 (s, 3H), 2.82 (d, J=9.54 Hz, 3H), 3.17 (d, J=4.02 Hz, 1H), 3.78(br. s., 1H), 3.95 (br. s., 2H), 4.70 (br. s., 1H), 5.40 (s, 2H), 7.55(d, J=8.03 Hz, 1H), 7.66 (d, J=8.03 Hz, 1H). Chiral purity(Method-XXVIII): retention time 5.85 min, 99.3% ee. LCMS: The compounddid not ionize well. The diastereomer-II was separated into twoindividual enantiomers by using similar SFC method as that ofdiastereomer-I. First eluted compound (retention time 8.61 min),designated as Intermediate 52A-III, was obtained (0.20 g, 5.00%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 1.64-1.82(m, 2H), 2.26 (s, 3H), 3.06 (d, J=11.04 Hz, 1H), 3.17 (d, J=5.52 Hz,1H), 3.52 (br. s., 1H), 3.81 (br. s., 2H), 3.97 (br. s., 1H), 4.82 (br.s., 1H), 5.39 (s, 2H), 7.56 (br. s., 1H), 7.59-7.65 (m, 1H). Chiralpurity (Method-XXVIII): retention time 8.61 min, 100% ee. LCMS: Thecompound did not ionize well. Second eluted compound (retention time9.82 min), designated as Intermediate 52A-IV, was obtained (0.21 g,5.20%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s,9H), 1.64-1.82 (m, 2H), 2.26 (s, 3H), 3.06 (d, J=11.04 Hz, 1H), 3.17 (d,J=5.52 Hz, 1H), 3.52 (br. s., 1H), 3.81 (br. s., 2H), 3.97 (br. s., 1H),4.82 (br. s., 1H), 5.39 (s, 2H), 7.56 (br. s., 1H), 7.59-7.65 (m, 1H).Chiral purity (Method-XXVIII): retention time 9.82 min, 97.80% ee. LCMS:The compound did not ionize well.

Intermediate 52-I

To a solution of Intermediate 52A-I (1.20 g, 3.45 mmol) in DCM (50 mL)at 0° C. was added 4N HCl in dioxane (12.95 mL, 51.8 mmol). Theresulting mixture was stirred at ambient temperature for 2 h. Thereaction mixture was concentrated to dryness, washed with diethylether(2×50 mL) and dried under reduced pressure to obtain Intermediate 52-I(0.90 g, 92.00%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm1.72-1.85 (m, 1H), 2.08 (d, J=13.05 Hz, 1H), 2.30 (s, 3H), 3.08 (d,J=9.04 Hz, 2H), 3.12-3.20 (m, 2H), 3.97 (br. s., 1H), 4.99 (br. s., 1H),5.40 (d, J=5.52 Hz, 2H), 7.61 (d, J=8.03 Hz, 1H), 7.70 (d, J=8.03 Hz,1H), 8.96 (br. s., 1H), 9.05 (br. s., 1H), (1 Exchangeable proton notobserved). LCMS (Method-D) retention time 0.395 min, [M+H] 248.0. Todetermine stereochemistry of Intermediate 52-I,5-((3R,4R)-1-(4-bromobenzoyl)-4-hydroxypiperidin-3-yl)-4-methylisobenzofuran-1(3H)-onewas prepared according to literature procedure (WO2011/012896, 2011),and absolute configuration was determined by single-crystal X-raydiffraction method.

Example 1-I:(R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile

To a solution of Intermediate 6 (0.05 g, 0.23 mmol) in MeOH (1 mL) wasadded Intermediate 3-I (0.05 g, 0.23 mmol) and the reaction mixture wasstirred at ambient temperature for 15 min. NaCNBH₃ (0.04 g, 0.71 mmol)was added and stirring was continued for 12 h at ambient temperature.The reaction mixture was diluted with water (15 mL) and extracted withethyl acetate (2×20 mL). The combined organic layer was washed withbrine (20 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by HPLC [XBridge C18 (19×150mm) 5 micron; Solvent A: 0.1% TFA; Solvent B: Acetonitrile, Gradient:10-100% B over 25 minutes, Flow: 15 mL/min, retention time 1.60 min, UV220 nm] to obtain Example 1-I (0.02 g, 17.10%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.86-1.96 (m, 1H), 2.20 (s, 3H), 2.23-2.29 (m, 1H), 2.58(s, 3H), 2.81 (d, J=11.74 Hz, 1H), 2.92 (d, J=11.49 Hz, 1H), 3.56 (s,2H), 3.71-3.81 (m, 1H), 3.99 (d, J=9.54 Hz, 1H), 4.81 (d, J=8.07 Hz,1H), 5.38 (d, J=4.89 Hz, 2H), 7.57-7.63 (m, 1H), 7.64-7.71 (m, 1H), 7.87(s, 1H), 7.99 (s, 1H), 8.55 (s, 1H), 8.83 (s, 1H). LCMS/HPLC (Method-A):retention time 1.25 min, [M+H]430.0, purity: 100%. (Method-B): retentiontime 1.90 min, [M+H] 430.0, purity: 98.3%. Chiral purity (Method-1):retention time 10.04 min, 100% ee,

Example 2-I:(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile

Example 2-I was prepared (0.11 g, 21.36%) as a white solid, by using asimilar synthetic protocol as that of Example 1-I and starting fromIntermediate 6 (0.25 g, 1.17 mmol) and Intermediate 2-I. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.79 (t, J=10.29 Hz, 1H), 2.03-2.18 (m, 1H), 2.25(s, 3H), 2.66-2.67 (m, 4H), 2.79 (t, J=9.04 Hz, 2H), 2.84-2.92 (m, 1H),2.94-3.05 (m, 1H), 3.45-3.59 (m, 2H), 4.06 (d, J=9.54 Hz, 1H), 5.36 (d,J=1.51 Hz, 2H), 7.63 (d, J=8.03 Hz, 1H), 7.76 (d, J=8.03 Hz, 1H), 7.85(s, 1H), 7.98 (s, 1H), 8.52 (s, 1H), 8.82 (s, 1H). HPLC (Method-F):retention time 5.62 min, purity: 98.55%. (Method-G): retention time 5.62min, purity: 98.55%. LCMS (Method-H): retention time 1.82 min, [M+H]429.0. Chiral purity (Method-VII): retention time 4.29 min, 100% ee.

Example 3-1(R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)pyridin-2-yl)benzo[d]oxazol-2(3H)-one

Example 3-I was prepared (0.006 g, 5.13%) as white solid, by using asimilar synthetic protocol as that of Intermediate 2B and starting fromIntermediate 8 (0.06 g, 0.24 mmol) and Intermediate 5-I. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.99 (t, J=10.76 Hz, 1H), 2.23 (s, 3H), 2.26-2.35(m, 1H), 2.79 (d, J=11.25 Hz, 1H), 2.90 (d, J=10.52 Hz, 1H), 3.42 (s,3H), 3.64 (s, 2H), 3.74-3.83 (m, 1H), 4.01 (d, J=11.49 Hz, 1H), 4.85 (d,J=8.80 Hz, 1H), 5.38 (d, J=3.67 Hz, 2H), 7.43 (d, J=8.56 Hz, 1H),7.60-7.66 (m, 1H), 7.66-7.71 (m, 1H), 7.83-7.92 (m, 2H), 7.96 (d, J=1.47Hz, 1H), 8.01 (d, J=8.56 Hz, 1H), 8.61 (s, 1H). LCMS/HPLC (Method-A):retention time 1.21 min, [M+H] 472.2, purity: 100%. (Method-B):retention time 1.83 min, [M+H] 472.2, purity: 99.40%. Chiral purity(Method-XVIII): retention time 24.29 min, 100% ee.

Example 45-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-3-methylbenzo[d]oxazol-2(3H)-one

Example 4 was prepared (0.01 g, 13.77%), by using Intermediate 4 (0.05g, 0.15 mmol) in a manner similar to synthetic protocol described forIntermediate 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.16 (br. s., 2H), 2.29(s, 3H), 2.33 (s, 1H), 2.65-2.73 (m, 1H), 2.90 (br. s., 1H), 3.01 (br.s., 1H), 3.39 (s, 3H), 3.63 (s, 2H), 3.68-3.80 (m, 1H), 5.40 (q, J=15.41Hz, 2H), 7.41 (d, J=8.56 Hz, 1H), 7.56 (dd, J=8.56, 2.20 Hz, 1H),7.62-7.68 (m, 2H), 7.69-7.71 (m, 1H), 7.74 (d, J=2.20 Hz, 1H), 8.44 (s,1H). LCMS/HPLC (Method-A): retention time 1.29 min, [M+H] 495.0, purity:94.70%. (Method-B): retention time 1.87 min, [M+H] 495.1, 95.90%.

Example 56-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Example 5 was prepared (0.01 g, 12.92%), by using Intermediate 6 (0.04g, 0.19 mmol) and Intermediate 4C in a manner similar to syntheticprotocol described for Example 1-I.

¹H NMR (300 MHz, CDCl₃) δ ppm 2.34 (s, 3H), 2.44 (br. s., 2H), 2.66 (s,3H), 3.04 (d, J=10.58 Hz, 1H), 3.22 (t, J=2.46 Hz, 1H), 3.64 (t, J=15.86Hz, 2H), 4.09-4.18 (m, 1H), 4.20-4.40 (m, 2H), 5.26-5.33 (m, 2H), 7.48(d, J=8.69 Hz, 1H), 7.80 (d, J=8.31 Hz, 1H), 7.87 (s, 1H), 7.99 (s, 1H),8.62 (s, 1H), 8.74 (s, 1H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −96.34,−110.26. LCMS/HPLC (Method-A): retention time 1.375 min, [M+H] 464.0,purity: 95.80%. (Method-B): retention time 2.11 min, [M+H] 464.0,95.20%.

Example 6-I:(R)-6-(5-methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Example 6-I was prepared (0.02 g, 22.08%), as an off-white solid, byusing a similar synthetic protocol as that of Example 1-I and startingfrom Intermediate 9 (0.05 g, 0.20 mmol) and Intermediate 2-I. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.87 (t, J=10.76 Hz, 1H), 2.14 (s, 1H), 2.26(s, 3H), 2.55 (s, 3H), 2.80 (d, J=10.76 Hz, 2H), 2.85-2.93 (m, 1H), 2.99(d, J=10.03 Hz, 1H), 3.40 (s, 2H), 3.95 (s, 3H), 4.09 (d, J=10.27 Hz,1H), 5.37 (s, 2H), 7.64 (d, J=8.07 Hz, 1H), 7.73-7.78 (m, 2H), 8.38 (s,1H), 8.74 (s, 1H), (Exchangeable proton not observed). LCMS/HPLC(Method-A): retention time 1.31 min, [M+H] 459, purity: 100%.(Method-B): retention time 1.78 min, [M+H] 459, purity: 99.40%. Chiralpurity (Method-XV): retention time 9.83 min, 82.80% ee.

Example 7-I:(R)-4-methyl-5-(4-((1-(2-methylthiazol-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one

Example 7-I was prepared (0.02 g, 17.25%) as a pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from Intermediate 14-I (0.10 g, 0.319 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.87-1.95 (m, 1H), 2.16-2.22 (m, 1H), 2.24 (s, 3H), 2.62(s, 3H), 2.80 (d, J=11.00 Hz, 1H), 2.91 (d, J=11.74 Hz, 1H), 3.49 (s,2H), 3.71-3.80 (m, 1H), 3.99 (dd, J=11.49, 2.20 Hz, 1H), 4.81 (dd,J=10.03, 2.20 Hz, 1H), 5.33-5.44 (m, 2H), 7.59-7.70 (m, 3H), 7.86 (s,1H), 8.33 (s, 1H). LCMS/HPLC (Method-A): retention time 1.06 min, [M+H]411.1, purity: 100%. (Method-B): retention time 1.52 min, [M+H] 411.1,purity: 99.60%. Chiral purity (Method-XV): retention time 11.36 min,100% ee.

Example 8-1(R)-4-cyclopropyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile

Example 8-I was prepared (0.003 g, 4.27%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from Intermediate 14-I (0.05 g, 0.16 mmol) and intermediate 10(0.05 g, 0.23 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02-1.11 (m, 2H), 1.26-1.40 (m, 2H),2.19-2.30 (m, 4H), 3.61 (s, 2H), 3.90 (d, J=11.49 Hz, 2H), 4.18 (d,J=11.25 Hz, 4H), 5.05 (br. s., 1H), 5.33-5.52 (m, 2H), 7.45 (s, 1H),7.63 (d, J=7.83 Hz, 1H), 7.74 (d, J=8.07 Hz, 1H), 7.98 (s, 1H),8.72-8.90 (m, 2H). LCMS/HPLC (Method-A): retention time 1.40 min, [M+H]456.1, purity: 100%. (Method-B): retention time 2.09 min, [M+H]456.1,purity: 94.50%. Chiral purity (Method-V): retention time 10.54 min, 100%ee.

Example 9-I:(R)-4-methyl-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile

To a solution of Intermediate 12-I (0.06 g, 0.149 mmol) in DCM (5 mL)was added dipyridyl-2-carbonate (0.03 mg, 0.15 mmol), TEA (0.04 mL, 0.29mmol) and the resulting reaction mixture was stirred at ambienttemperature for 16 h. The reaction mixture was concentrated underreduced pressure. The residue was purified by preparative HPLC [XBridgeC18 (19×150 mm) 5-am; Solvent A: 10 mM Ammonium Acetate, Solvent B:methanol, Gradient: 15-57% B over 20 min, then a 5-minute hold at 100%B; Flow: 15 mL/min, retention time 2.70 min, UV 220 nm] to obtainExample 9-I (0.13 g, 19.34%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.23 (s, 3H), 2.64 (s, 3H), 4.10 (t, J=9.04 Hz, 1H),4.28-4.53 (m, 3H), 5.35-5.48 (m, 2H), 5.97 (dd, J=9.04, 7.03 Hz, 1H),7.55 (d, J=8.03 Hz, 1H), 7.74 (d, J=7.53 Hz, 1H), 7.89 (s, 1H), 8.00 (d,J=1.00 Hz, 1H), 8.64 (s, 1H), 8.85 (s, 1H). LCMS/HPLC (Method-A):retention time 1.69 min, [M+H] 430.1, purity: 95.30%. (Method-B):retention time 1.70 min, [M+H] 430.1, purity: 94.30%. Chiral purity(Method-X): retention time 5.58 min, 100% ee.

Example 10-I:(R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxomorpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile

To a stirred solution of Intermediate 13-I (0.05 g, 0.11 mmol) in THE(10 mL) was added tri-n-butylphosphine (0.08 mL, 0.32 mmol) followed bydiisopropyl azodicarboxylate (0.04 mL, 0.22 mmol). The resultingreaction mixture was stirred at ambient temperature for 1 h and dilutedwith water (30 mL). The reaction mixture was extracted with ethylacetate (3×25 mL). The combined organic layers were washed with brine(25 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by preparative HPLC [XBridgephenyl (19×250 mm) 5 micron; Solvent A: 10 mM CH₃COONH₄—PH-4.5, SolventB: Acetonitrile; Gradient: 40-65% over 24 min; Flow: 17 mL/min,retention time 11.24 min, UV 254 nm] to obtain Example 10-I (0.001 g,2.50%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29 (s, 3H), 2.59 (s, 3H),3.36-3.46 (m, 1H), 3.57 (dd, J=12.23, 3.18 Hz, 1H), 4.28-4.51 (m, 3H),4.60 (d, J=14.92 Hz, 1H), 5.29 (dd, J=10.52, 3.42 Hz, 1H), 5.34-5.50 (m,2H), 7.58-7.66 (m, 1H), 7.67-7.76 (m, 1H), 7.91 (s, 1H), 8.01 (s, 1H),8.65 (s, 1H), 8.85 (s, 1H). LCMS/HPLC (Method-A): retention time 1.67min, [M+H] 444.1, purity: 100%. (Method-B): retention time 1.65 min,[M+H] 444.1, purity: 100%. Chiral purity (Method-1): retention time22.89 min, 100% ee.

Example 11-I(R)-4-methoxy-6-(4-(2-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl)nicotinonitrile

Example 11-I was prepared (0.05 g, 32.65%), by using a similar syntheticprotocol as that of Example 1-I and starting from Intermediate 15 (0.07g, 0.31 mmol) and Intermediate 3-I. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.85-2.00 (m, 1H), 2.22-2.33 (m, 3H), 2.60 (br. s., 3H), 2.71 (d, J=5.87Hz, 2H), 2.89 (d, J=11.98 Hz, 1H), 2.99 (d, J=11.49 Hz, 1H), 3.75 (t,J=11.13 Hz, 1H), 4.00 (d, J=10.03 Hz, 1H), 4.10 (s, 3H), 4.80 (d,J=10.03 Hz, 1H), 5.30-5.51 (m, 2H), 7.58 (s, 1H), 7.60-7.76 (m, 2H),7.84 (s, 1H), 8.50 (s, 1H), 8.73 (s, 1H). LCMS/HPLC (Method-A):retention time 1.29 min, [M+H] 460.1, purity: 98.12%. (Method-B):retention time 1.95 min, [M+H] 460.1, purity: 97.20%. Chiral purity(Method-1): retention time 10.17 min, 100% ee.

Example 12-I:(R)-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile

To a stirred solution of Intermediate 16 (0.04 g, 0.18 mmol) andIntermediate 3-I (0.04 g, 0.18 mmol) in ACN (5 mL) was added K₂CO₃ (0.07g, 0.54 mmol) followed by KI (0.003 g, 0.02 mmol). The reaction mixturewas stirred at ambient temperature for 14 h, diluted with water (25 mL)and extracted with ethyl acetate (3×15 mL). The combined organic layerwas washed with brine (15 mL), dried over anhydrous sodium sulfate andconcentrated. The residue was purified by HPLC [XBridge C18 (19×150 mm)5 micron; Solvent A: 0.1% trifluoroacetic acid; Solvent B: Acetonitrile;Gradient: 5-32% over 20 min, Flow: 15 mL/min, retention time 10.63 min,UV 220 nm] to obtain Example 12-I (0.058 g, 76.31%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.18 (t, J=10.64 Hz, 1H), 2.28 (s, 3H), 2.39-2.48 (m,1H), 2.89 (d, J=11.00 Hz, 1H), 3.05 (d, J=11.49 Hz, 1H), 3.69-3.84 (m,1H), 3.96-4.12 (m, 3H), 4.85 (dd, J=9.90, 2.08 Hz, 1H), 5.31-5.47 (m,2H), 7.57-7.63 (m, 1H), 7.65-7.73 (m, 1H), 8.35 (dd, J=8.31, 0.98 Hz,1H), 8.57 (dd, J=8.19, 2.08 Hz, 1H), 9.23 (dd, J=2.08, 0.86 Hz, 1H).LCMS/HPLC (Method-A): retention time 1.26 min, [M+H] 418.1, purity:100%. (Method-B): retention time 1.41 min, [M+H]418.0, purity: 100%.Chiral purity (Method-VII): retention time 17.41 min, 100% ee.

Example 13-I:(R)-4-methyl-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile

Example 13-I was prepared (0.02 g, 21.80%) by using a similar syntheticprotocol as that of Example 12-I and starting from Intermediate 17 (0.04g, 0.17 mmol) and Intermediate 2-I. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.00-2.10 (m, 1H), 2.29 (s, 3H), 2.63 (s, 4H), 2.89 (t, J=10.76 Hz, 4H),2.97-3.06 (m, 1H), 4.00 (s, 2H), 4.11 (d, J=8.56 Hz, 1H), 5.39 (s, 2H),7.65 (d, J=8.07 Hz, 1H), 7.77 (d, J=7.83 Hz, 1H), 8.32 (s, 1H), 9.11 (s,1H). LCMS/HPLC (Method-A): retention time 1.12 min, [M+H] 431.1, purity:100%. (Method-B): retention time 1.66 min, [M+H] 431.1, purity: 99.56%.Chiral purity (Method-T): retention time 8.77 min, 100% ee.

Example 14-I:(R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)nicotinonitrile

Example 14-I was prepared (0.10 g, 20.13%) by using a similar syntheticprotocol as that of Example 1-I and starting from Intermediate 11 (0.25g, 1.10 mmol) and Intermediate 2-I.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.89 (br. s., 1H), 2.19 (br. s., 1H),2.27 (s, 3H), 2.81-3.05 (m, 5H), 3.50 (s, 2H), 4.03-4.14 (m, 4H), 5.37(s, 2H), 7.59 (s, 1H), 7.65 (d, J=8.07 Hz, 1H), 7.78 (d, J=8.07 Hz, 1H),7.95 (s, 1H), 8.58 (d, J=1.22 Hz, 1H), 8.74 (s, 1H). LCMS/HPLC(Method-A): retention time 0.99 min, [M+H] 445.1, purity: 100%.(Method-B): retention time 1.28 min, [M+H] 445.0, purity: 99.56%. Chiralpurity (Method-): retention time 7.10 min, 84.55% ee.

Example 15-I:(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile

Example 15-I was prepared (0.008 g, 12.95%) as a white solid, by using asimilar synthetic protocol as that of Example 1-I and starting fromIntermediate 6 (0.03 g, 0.14 mmol) and Intermediate 19-I. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.22 (s, 3H), 2.41 (dd, J=11.62, 6.24 Hz, 1H), 2.56(s, 3H), 2.90 (dd, J=11.98, 4.16 Hz, 1H), 3.05-3.22 (m, 2H), 3.47-3.65(m, 2H), 4.94 (br. s., 1H), 5.21-5.34 (m, 1H), 5.36-5.46 (m, 1H), 7.56(d, J=8.07 Hz, 1H), 7.68-7.80 (m, 2H), 7.96 (s, 1H), 8.18 (s, 1H), 8.28(s, 1H), 8.76 (s, 1H). LCMS/HPLC (Method-A): retention time 1.23 min,[M+H] 443.1, purity: 96.48%. (Method-B): retention time 1.51 min, [M+H]443.1, purity: 100%. Chiral purity (Method-T): retention time 12.48 min,92% ee.

Example 16-I:(R)-4-methyl-5-(4-((6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one

Example 16-I was prepared (0.01 g, 9.26%), by using a similar syntheticprotocol as that of Intermediate 23-I and starting from Intermediate 20(0.05 g, 0.26 mmol) and Intermediate 3-I. ¹H NMR (400 MHz, DMSO-d₆) δppm 2.17 (s, 3H), 2.22 (s, 3H), 2.23-2.36 (m, 2H), 2.77 (d, J=11.25 Hz,1H), 2.87 (d, J=11.98 Hz, 1H), 3.61 (s, 2H), 3.69-3.85 (m, 1H), 3.99 (d,J=9.54 Hz, 1H), 4.82 (d, J=7.58 Hz, 1H), 5.26-5.45 (m, 2H), 7.54-7.75(m, 4H), 7.92 (dd, J=8.31, 2.20 Hz, 1H), 8.39 (s, 2H). LCMS/HPLC(Method-A): retention time 0.83 min, [M+H] 405.1, purity: 99.20%.(Method-B): retention time 1.56 min, [M+H] 405.0, purity: 95.99%. Chiralpurity (Method-X): retention time 12.55 min, 96.10% ee

Example 17-I:(R)-4-methoxy-5′-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-[2,2′-bipyridine]-5-carbonitrile

A solution of Intermediate 23-I (0.15 g, 0.35 mmol) in THE (20 mL) at70° C. was added 1,1′-carbonyldiimidazole (0.06 g, 0.38 mmol) and theresulting reaction mixture was stirred for 1 h. The reaction mixture wascooled to ambient temperature and was evaporated under reduced pressure.The residue was diluted with water (15 mL) and extracted with DCM (3×15mL). The combined organic layers were washed with brine (10 mL), driedover anhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by HPLC [Intertsil ODS (250×10 mm) 5 micron;Solvent A: 10 mM NH₄OAc in H₂O, Solvent B: Acetonitrile, Gradient:20-65% over 14 min, Flow: 17 mL/min retention time 15.06 min, UV 254 nm]to obtain Example 17-I (0.02 g, 8.68%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.22 (s, 3H), 4.03-4.07 (m, 2H), 4.11 (s, 3H), 4.51 (d, J=16.00 Hz, 1H),4.62 (d, J=16.00 Hz, 1H), 5.22-5.48 (m, 2H), 6.02 (t, J=8.19 Hz, 1H),7.59 (d, J=8.56 Hz, 1H), 7.76 (d, J=8.07 Hz, 1H), 7.95 (d, J=8.07 Hz,1H), 8.14 (s, 1H), 8.43 (d, J=8.07 Hz, 1H), 8.70 (s, 1H), 8.92 (s, 1H).LCMS/HPLC: (Method-A) retention time: 1.59 min, [M+1]: 457.1, purity:100%. (Method-B) retention time: 1.65 min, [M+1]: 457.0, purity: 100%.Chiral purity (Method-XVI): retention time 6.39 min, 100% ee

Example 18-I:6-(4-(1-hydroxy-2-((R)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile(Diastereomer-I & II

To a solution of Intermediate 24 (0.12 g, 0.53 mmol) in EtOH (10 mL) wasadded Intermediate 3-I (0.12 g, 0.53 mmol) and the resulting reactionmixture was stirred at 85° C. for 48 h. Ethanol was evaporated underreduced pressure and residue was purified by HPLC [XBridge phenyl(250×19 ID) 5 micron; Solvent A: 10 mM NH₄HCO₃—PH-9.5, Solvent B:Acetonitrile; Gradient: 0-62% over 15 min; Flow: 16 mL/min, UV 254 nm].First eluted compound (retention time 15.33 min), designated as Example18-I Dia-I (Diastereomer-1) was obtained (0.009 g, 19.00%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.01-2.08 (m, 1H), 2.25 (s, 3H), 2.31-2.34 (m, 1H),2.36 (d, J=3.01 Hz, 1H), 2.58 (s, 3H), 2.65-2.68 (m, 1H) 2.85 (d,J=10.80 Hz, 1H), 3.07 (d, J=10.80 Hz, 1H), 3.72-3.80 (m, 1H), 3.95-4.03(m, 1H), 4.79 (d, J=9.54 Hz, 1H), 4.85 (d, J=6.53 Hz, 1H), 5.22 (d,J=5.02 Hz, 1H), 5.39 (d, J=4.52 Hz, 2H), 7.62 (d, J=8.00 Hz, 1H), 7.67(d, J=8.00 Hz, 1H), 7.90 (s, 1H), 7.99 (s, 1H), 8.54 (s, 1H), 8.84 (s,1H). LCMS (Method-H): retention time 1.93 min, [M+H] 460.1, purity:98.60%. HPLC (Method-F): retention time 5.12 min, purity: 99.14%.(Method-G): retention time 6.03 min, purity: 99.42%. Chiral purity(Method-X): retention time 10.19 min, 97.70% ee.

Second eluted compound (retention time 17.02 min), designated as Example18-I Dia-II (Diastereomer-II) was obtained (0.008 g 16.00%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.01-2.08 (m, 1H), 2.25 (s, 3H), 2.31-2.34 (m, 1H),2.36 (d, J=3.01 Hz, 1H), 2.58 (s, 3H), 2.65-2.68 (m, 1H) 2.96 (t,J=11.80 Hz, 2H), 3.72-3.80 (m, 1H), 3.95-4.03 (m, 1H), 4.79 (d, J=9.54Hz, 1H), 4.85 (d, J=6.53 Hz, 1H), 5.22 (d, J=5.02 Hz, 1H), 5.39 (d,J=4.52 Hz, 2H), 7.62 (d, J=8.00 Hz, 1H), 7.67 (d, J=8.00 Hz, 1H), 7.90(s, 1H), 7.99 (s, 1H), 8.54 (s, 1H), 8.84 (s, 1H). LCMS (Method-H):retention time 1.92 min, [M+H] 460.1, purity: 95.43%. HPLC (Method-F):retention time 5.11 min, purity: 90.01%. (Method-G): retention time 6.00min, purity: 88.76%. Chiral purity (Method-X): retention time 12.55 min,96.10% ee.

Example 19-I:(R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)thiazol-2-yl)benzo[d]oxazol-2(3H)-one

Example 19-I was prepared (0.01 g, 16.97%), by using a similar syntheticprotocol as that of Example 3-I and starting from Intermediate 25-I(0.10 g, 0.12 mmol) and Intermediate 8. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.94-2.07 (m, 1H), 2.24 (s, 3H), 2.28-2.37 (m, 1H), 2.83-2.91 (m, 1H),2.96 (d, J=11.74 Hz, 1H), 3.42 (s, 3H), 3.72-3.83 (m, 1H), 3.87 (s, 2H)4.03 (d, J=9.29 Hz, 1H), 4.83 (s, 1H), 5.38 (d, J=2.45 Hz, 2H), 7.44 (d,J=8.31 Hz, 1H), 7.67 (s, 1H) 7.69 (s, 1H) 7.70 (dd, J=8.00 Hz, 1.60 Hz,1H), 7.75 (s, 1H) 7.79 (d, J=1.71 Hz, 1H). LCMS/HPLC (Method-A):retention time 1.23 min, [M+H] 478.1, purity: 99.56%. (Method-B):retention time 1.89 min, [M+H]478.0, purity: 99.59%. Chiral purity(Method-X): retention time 9.67 min, 100% ee.

Example 20-I:(R)-3-methyl-5-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholine-4-carbonyl)thiazol-2-yl)benzo[d]oxazol-2(3H)-one

Example 20-I was prepared (0.01 g, 5.29%), by using a similar syntheticprotocol as that of Example 3-I and starting from Intermediate 26-I(0.15 g, 0.35 mmol) and Intermediate 8.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.08 (s, 3H), 2.20-2.37 (m, 3H), 3.43(s, 3H), 3.83 (dd, J=11.49, 8.80 Hz, 1H), 4.12 (d, J=9.78 Hz, 1H),4.15-4.31 (br. s., 1H), 4.94 (d, J=10.03 Hz, 1H), 5.42 (br. s., 2H),7.49 (d, J=8.07 Hz, 1H), 7.66-7.83 (m, 3H), 7.87 (d, J=1.71 Hz, 1H),8.26 (s, 1H). LCMS/HPLC (Method-A): retention time 1.71 min, [M+H]492.1, purity: 96.82%. (Method-B): retention time 1.73 min, [M+H] 492.0,purity: 97.44%. Chiral purity (Method-XVI): retention time 3.40 min,100% ee.

Example 21-I:(R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)thiazol-2-yl)-1H-imidazole-4-carbonitrile

Example 21-I was prepared (0.006 g, 9.11%) as a white solid, by using asimilar synthetic protocol as that of Example 1-I and starting fromIntermediate 27 (0.03 g, 0.17 mmol) and Intermediate 2-I. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.84-2.00 (m, 1H), 2.26 (s, 3H), 2.78-2.94 (m, 4H),3.02 (d, J=12.23 Hz, 1H), 3.69-3.85 (m, 2H), 4.07 (d, J=8.56 Hz, 1H),5.27-5.41 (m, 2H), 7.60 (s, 1H), 7.66 (d, J=7.83 Hz, 1H), 7.77 (d,J=7.58 Hz, 1H), 8.64 (s, 1H), 8.85 (s, 1H), (Exchangeable proton notobserved). LCMS/HPLC (Method-A): retention time 1.07 min, [M+H] 421.1,purity: 100%. (Method-B): retention time 1.32 min, [M+H] 421.0, purity:100%. Chiral purity (Method-XVIII): retention time 11.69 min, 100% ee.

Example 22-I:(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile

Example 22-I was prepared (0.01 g, 10.83%), by using a similar syntheticprotocol as that of Example 1-I and starting from Intermediate 28 (0.04g, 0.19 mmol) and Intermediate 2-I (0.05 g, 0.206 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.87-1.95 (m, 1H), 2.17-2.23 (m, 1H), 2.26 (s, 3H),2.61 (s, 3H), 2.80-3.03 (m, 4H), 3.77 (s, 2H), 4.10 (d, J=8.07 Hz, 1H),5.37 (d, J=2.45 Hz, 2H), 7.65 (d, J=8.07 Hz, 1H), 7.77 (d, J=8.07 Hz,1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.92 (s, 1H), (Exchangeable protonpresent). LCMS/HPLC (Method-A): retention time 1.15 min, [M+H] 430,purity: 96.70%. (Method-B): retention time 1.36 min, [M+H] 430, purity:100%. Chiral purity (Method-XVIII): retention time 26.46 min, 100% ee.

Example 23-I:(R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile

Example 23-I was prepared (0.008 g, 8.83%), by using a similar syntheticprotocol as that of Example 1-I and starting from Intermediate 30 (0.04g, 0.19 mmol) and Intermediate 2-I. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.86-1.95 (m, 1H), 2.15-2.29 (m, 4H), 2.64 (s, 3H), 2.81-3.03 (m, 4H),3.75 (s, 2H), 4.09 (d, J=9.54 Hz, 1H), 5.32-5.43 (m, 2H), 7.64 (d,J=7.83 Hz, 1H), 7.76 (d, J=7.83 Hz, 1H), 8.28 (s, 1H), 8.77 (s, 1H),8.98 (s, 1H), (Exchangeable proton not observed). LCMS/HPLC (Method-A):retention time 1.43 min, [M+H] 430.0, purity: 98.88%, (Method-B):retention time 1.23 min, [M+H] 430.1, purity: 98.70%. Chiral purity(Method-IX): retention time 12.83 min. 98.50% ee.

Example 24-I: Methyl(R)-4-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a stirred solution of Example 2-I (0.03 g, 0.06 mmol) in DCM (3.00mL) at 0° C. was added TEA (0.03 mL, 0.18 mmol) followed by methylchloroformate (4.52 μL, 0.06 mmol). The resulting reaction mixture wasstirred at ambient temperature for 18 h, diluted with water (15 mL) andextracted with DCM (3×15 mL). The combined organic extracts were washedwith brine (15 mL), dried over sodium sulfate and evaporated underreduced pressure. The residue was purified by HPLC [XBridge C18 (19×150mm) 5 micron; Solvent A: 10-mM ammonium acetate; Solvent B:Acetonitrile, Gradient: 20-100% B over 15 minutes, Flow: 15 mL/min,retention time 2.80 min, UV 220 nm] to obtain Example 24-I (0.003 g,9.15%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.19 (br. s., 1H), 2.20-2.26 (m,3H), 2.46 (d, J=4.89 Hz, 1H), 2.56 (s, 3H), 2.89-3.05 (m, 2H), 3.43-3.54(m, 2H), 3.57 (s, 4H), 3.87 (d, J=11.98 Hz, 1H), 5.25-5.33 (m, 1H),5.34-5.43 (m, 2H), 7.69 (d, J=8.07 Hz, 1H), 7.76 (s, 1H), 7.95 (s, 1H),8.02 (d, J=8.07 Hz, 1H), 8.37 (s, 1H), 8.78 (s, 1H). LCMS/HPLC(Method-A): retention time 1.26 min, [M+H]487.1, purity: 98.94%.(Method-B): retention time 2.02 min, [M+H] 487.1, purity: 100%. Chiralpurity (Method-X): retention time 25.56 min, 86.55% ee.

The examples in Table 1 were synthesized using procedures in Example 1to 24-I.

HPLC/ LCMS Method: Ex- LCMS RT am- (M + (min.), ple Structure Name H)⁺Purity NMR 1-II

(8)-4-methyl- 6-(4-((2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl) morpholino) methyl)- 1H-pyrazol-1-yl) nicotinonitrile 468.1 A:1.27, 97.90% B: 1.89, 97.30% XVIII: 18.26, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.86-1.96 (m, 1H), 2.18-2.29 (m, 4H), 2.58 (s, 3H), 2.81(d, J = 11.74 Hz, 1H), 2.92 (d, J = 11.49 Hz, 1H), 3.56 (s, 2H),3.71-3.81 (m, 1H), 3.99 (d, J = 9.54 Hz, 1H), 4.81 (d, J = 8.07 Hz, 1H),5.38 (d, J = 4.89 Hz, 2H), 7.57-7.63 (m, 1H), 7.64-7.71 (m, 1H), 7.87(s, 1H), 7.99 (s, 1H), 8.55 (s, 1H), 8.83 (s, 1H). 25-I

(R)-3-methyl- 5-(4-((2- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) methy1)-1H- pyrazol-1-yl) benzo[d] oxazol-2(3H)- one461.1 A: 1.16, 96.80% B: 1.66, 98.20% XIV: 11.59, 100% ee 400 MHz,DMSO-d₆ δ 2.29 (s, 3H), 3.03-3.41 (m, 3H), 3.39 (s, 3H), 3.96 (d, J =12.40 Hz, 2H), 4.23-4.32 (m, 3H), 5.11 (d, J = 10.40 Hz, 1H), 5.43 (d, J= 4.00 Hz, 2H), 7.47 (d, J = 8.80 Hz, 1H), 7.57 (dd, J = 2.40, 8.60 Hz,1H), 7.67 (d, J = 8.00 Hz, 1H), 7.73 (d, J = 2.00 Hz, 1H), 7.77 (d, J =7.60 Hz, 1H), 7.89 (s, 1H), 8.62 (s, 1H). 26-I

(R)-6-(5- methoxy-4- ((2-(4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl) morpholino) methyl)-1H- pyrazol-1-yl)- 4-methyl- nicotinonitrile460.1 A: 1.40, 100% B: 2.12, 100% XIV: 11.66, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.28 (s, 3H), 2.58 (s, 3H), 3.01-3.26 (m, 3H), 3.83-3.95(m, 1H), 4.01 (s, 3H), 4.10-4.31 (m, 3H), 4.99-5.12 (m, 1H), 5.42 (d, J= 3.51 Hz, 2H), 7.65 (s, 1H), 7.72-7.77 (m, 1H), 7.82 (s, 1H), 8.67-8.78(m, 1H), 8.81 (s, 1H), 10.15- 10.34 (m, 1H). 27-I

(R)-4-methoxy- 6-(4- ((2-(4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) methyl)-1H- imidazol- 1-yl) nicotinonitrile 446.1 A:1.57, 100% B: 1.19, 99.86% V: 8.64, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 1.98-2.0 ( m, 1H), 2.25 (s, 3H), 2.27- 2.36 (m, 1H), 2.79-2.90 (m,1H), 2.95- 3.02 (m, 1H), 3.55 (br. s., 2H), 3.71- 3.81 (m, 1H),3.96-4.03 (m, 1H), 4.10 (s, 3H), 4.80-4.83 (m, 1H), 5.39 (d, J = 4.28Hz, 2H), 7.58-7.64 (m, 2H), 7.65-7.69 (m, 1H), 7.99 (s, 1H), 8.61 (s,1H), 8.75 (s, 1H). 28-I

(R)-6-(4-((2-(4- methyl-1-oxo- 1,3-dihydroiso- benzofuran-5-yl)morpholino) methyl)-1H- imidazol-1-yl) nicotinonitrile 416.1 A: 1.43,96.32% V: 8.62, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.93-2.03 (m,1H), 2.25 (s, 3H), 2.26- 2.34 (m, 1H), 2.82-2.88 (m, 1H), 2.93- 3.01 (m,1H), 3.54 (s, 2H), 3.71-3 .80 (m, 1H), 3.94-401 (m, 1H), 4.79-4.84 (m,1H), 5.38 (d, J = 4.46 Hz, 2H), 7.59- 7.63 (m, 2H), 7.92 (s, 1H), 8.02(d, J = 8.68 Hz, 1H), 8.50 (d, J = 2.26 Hz, 1H), 8.59 (d, J = 1.10 Hz,1H), 8.96 (d, J = 2.08 Hz, 1H). 29-I

(R)-3-methyl- 5-(4-((2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) methyl)- 1H-imidazol- 1-yl) benzo[d] oxazol-2(3H)- 461.1A: 1.43, 98.01% B: 1.08, 99.47% V: 10.25, 99.38% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.95-2.03 (m, 1H), 2.25 (s, 3H), 2.84- 2.91 (m, 1H),2.97-3.03 (m, 1H), 3.38 (s, 3H), 3.39-3.40 (m, 1H), 3.50-3.53 (m, 2H),3.71-3.81 (m, 1H), 3.96-4.03 (m, 1H), 4.81 (dd, J = 10.12, 1.80 Hz, 1H),5.33-5.35 (m, 2H), 7.36 (d, J = 2.26 Hz, 1H), 7.39 (d, J = 2.20 Hz, 1H),7.60- 7.69 (m, 4H), 8.17 (d, J = 1.22 Hz, 1H). one 30-I

(R)-4-methyl- 6-(5-((2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) methyl)-1,3,4- oxadiazol-2-yl) nicotinonitrile 432.1 A:1.39, 98.15% B: 1.54, 97.20% X: 6.62, 100% ee ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.22-2.33 (m, 4H), 2.57 (br. s., 1H), 2.63 (s, 3H), 2.96 (d, J =10.76 Hz, 1H), 3.11 (d, J = 11.74 Hz, 1H), 3.75-3 .86 (m, 1H), 4.04 (d,J = 8.80 Hz, 1H), 4.13 (br. s., 2H), 4.79-4.93 (m, 1H), 5.40 (d, J =2.93 Hz, 2H), 7.58-7.66 (m, 1H), 7.66-7.75 (m, 1H), 8.32 (s, 1H), 9.12(s, 1H). 31-I

(R)-4-methyl- 6-(4-(2-(2- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-441.1 A: 1.84, 99.37% B: 2.04, 99.95% XIX: 9.24, ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.86-2.00 (m, 1H), 2.17-2.26 (m, 1H), 2.28 (s, 3H),2.58-2.64 (m, 4H), 2.68-2.77 (m, 2H), 2.83-2.92 (m, 2H), 2.99 (d, J =11.25 Hz, 1H), 3.69- 3.83 (m, 1H), 4.00 (d, J = 11.00 Hz,5-yl)morpholino) 100% 1H), 4.80 (d, J = 7.83 Hz, 1H), 5.29- ethyl)-1H-ee 5.46 (m, 2H), 7.66 (q, J = 8.07 Hz, 2 pyrazol-1-yl) H), 7.83 (s, 1H),7.96 (s, 1H), 8.50 (s, nicotinonitrile 1H), 8.79-8.87 (m, 1H). 32-I

(R)-4-methoxy- 6-(5- ((2-(4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) 463.1 A: 1.31, 100% B: 1.98, 99.23% XV: 11.34, 100% ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.02 (t, J = 10.64 Hz, 1H), 2.22 (s, 3 H),2.28-2.37 (m, 1H), 2.82-3.00 (m, 2H), 3.68-3.88 (m, 1H), 3.90 (s, 2H),4.02 (d, J = 13.21 Hz, 1H), 4.13 (s, 3H), 4.84 (d, J = 7.83 Hz, 1H),5.30-5.45 (m, 2H) 7.63 (s, 1H), 7.66-7.72 (m, 1H), methyl) ee 7.84 (s,1H), 7.90-8.01 (m, 1H), 8.87 thiazol-2-yl) (s, 1H). nicotinonitrile 33-I

(R)-4-methyl- 6-(5-(2- (4-methyl-1- oxo-1,3-di- hydroiso- benzofuran-5-yl)morpholine-4- 461.2 A: 1.61, 99.48% A: 1.62, 100% V: 16.99, 100% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H), 2.27 (br. s., 2H), 2.32-2.36 (m, 1H), 2.63 (s, 3H), 2.66-2.70 (m, 1H), 3.79-3.88 (m, 1H), 4.11(br. s., 1H), 4.95 (d, J = 9.05 Hz, 1H), 5.41 (br. s., 2H), 7.68-7.76(m, 2H), 8.27 (s, 1H), 8.40 (s, 1H), 9.03 (s, 1H). carbonyl)thiazol-2-yl) nicotinonitrile 34-I

(R)-4-methoxy- 6-(5-(2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl) 477.1 A: 1.82, 96.63% B: 1.81, 96.20% V: 17.05, 100% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H), 2.27 (br s., 2H), 2.31-2.35 (m,1H), 2.67 (br. s., 1H), 3.83 (t, J = 11.62 Hz, 1H), 4.04-4.11 (m, 1H),4.14 (s, 3H), 4.94 (d, J = 7.58 Hz, 1H), 5.40 (br. s., 2H), 7.65-7.78(m, 2H), 7.90 (s, 1H), 8.39 (s, 1H), 8.92 (s, 1H). morpholine-4-carbonyl) thiazol-2-yl) nicotinonitrile 35-I

(R)-4-methoxy- 5′-((2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) methyl)-[2,2′- bipyridine]-5- carbonitrile 457.1 A: 1.27,94.23% B: 1.95, 95.37% X: 10.00, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.24 (s, 3H), 2.27-2.36 (m, 1H), 2.76- 2.85 (m, 1H), 2.89-2.95 (m, 1H),3.68- 3.77 (m, 1H), 3.78 (br. s., 2H), 3.95- 4.05 (m, 1H), 4.64 (d, J =5.02 Hz, 1H), 4.13 (s, 3H), 4.98 (br. s., 1H), 5.34-5.47 (m, 2H), 7.64(d, J = 8.07 Hz, 1H), 7.72 (d, J = 7.34 Hz, 1H), 8.06 (br. s., 1H), 8.16(s, 1H), 8.48 (d, J = 8.31 Hz, 1H), 8.77 (br. s., 1H), 8.94 (s, 1H).36-I

(R)-4-methyl- 5-(4-((2- (4-methyl-1H- imidazol-1-yl) thiazol-5-yl)methyl) 411.1 A: 0.88, 96.07% B: 1.59, 94.02% XIV: 6.91, 100% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.16 (s, 3H), 2.24 (s, 3H), 2.22-2.43 (m, 2H),2.85 (d, J = 11.00 Hz, 1H), 2.95 (d, J = 11.25 Hz, 1H), 3.73 (d, J =9.78 Hz, 1H), 3.80 (s, 2H), 4.02 (d, J = 9.78 Hz, 1H), 4.80 (d, J = 7.83Hz, 1H) 5.33- morpholin-2-yl) 5.47 (m, 2H), 7.49 (s, 2H), 7.61 (d, J =isobenzofuran-1 8.0. Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), (3H)-one 8.24(s, 1H). 37-I

(R)-1-(5-((2- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)morpholino) methyl)pyridin- 390.0 A: 0.92, 95.02% B: 1.18, 95.73% X:2.76, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H), 2.24-2.36(m, 2H), 2.77 (d, J = 11.49 Hz, 1H), 2.89 (d, J = 11.74 Hz, 1H), 3.66(s, 2H), 3.72-3 .86 (m, 1H), 4.00 (d, J = 11.74 Hz, 1H), 4.75- 4.93 (m,1H), 5.29-5.46 (m, 2H), 7.52- 7.73 (m, 2H), 7.88 (d, J = 8.31 Hz, 1H),8.05 (dd, J = 8.31, 2.20 Hz, 1H), 8.50 2-yl)-1H- (d, J = 2.20 Hz, 1H),8.74 (d, J = 1.22 imidazole-4- Hz, 1H), 8.91 (d, J = 1.22 Hz, 1H).carbonitrile 38-I

(R)-4-methyl- 5-(4-((1- (thiophen-3-yl)- 1H- pyrazol-4-yl) methyl)morpholin- 2-yl) isobenzofuran- 1(3H)-one 396.2.0 A: 0.96 96.60%, B:1.50, 97.10% XVIII: 9.15, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.83-1.96 (m, 1H), 2.18-2.21 (m, 1H), 2.24 (s, 3H), 2.81 (d, 11.49 Hz,1H), 2.92 (d, J = 11.49 Hz, 1H), 3.50 (br. s., 2H), 3.69-3.82 (m, 1H),3.99 (d, J = 11.74 Hz, 1H), 4.81 (d, J = 8.80 Hz, 1H), 5.34-5.44 (m,2H), 7.50-7.56 (m, 1H), 7.58-7.70 (m, 5H), 8.29 (s, 1H). 39-I

(R)-4-methyl- 5-(4-((1- (pyrazin-2- yl)-1H- pyrazol-4- yl)methyl)morpholin- 2-yl) isobenzo- furan- 392.2 A: 0.77, 95.20% B: 1.31, 95.20%XVIII: 21.35, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.83-1.96 (m, 1H),2.18-2.21 (m, 1 H), 2.24 (s, 3H), 2.81 (d, J = 11.49 Hz, 1H), 2.92 (d, J= 11.49 Hz, 1H), 3.50 (br. s., 2H), 3.69-3.82 (m, 1H), 3.99 (d, J =11.74 Hz, 1H), 4.82 (dd, J = 10.03, 2.20 Hz, 1H), 5.33-5.45 (m, 2H),7.57- 7.69 (m, 2H), 7.87 (s, 1H), 8.49-8.56 (m, 2H), 8.60 (d, J = 2.45Hz, 1H), 9.20 (d, J = 1.22 Hz, 1H). 1(3H)-one 40-I

(R)-4-(4- ((2-(4-methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)morpholino) methyl)-1H- pyrazol-1-yl) benzonitrile 415.2 A: 1.00, 96.90%B: 1.55, 96.50% XVIII: 11.29, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.92 (t, J = 10.76 Hz, 1H), 2.18-2.21 (m, 1H), 2.24 (s, 3H), 2.82 (d, J= 11.25 Hz, 1H), 2.93 (d, J = 10.76 Hz, 1H), 3.53 (s, 2H), 3.71-3.81 (m,1H), 3.99 (d, J = 9.29 Hz, 1H), 4.81 (d, J = 7.83 Hz, 1H), 5.32-5.43 (m,2H), 7.58-7.70 (m, 2H), 7.79 (s, 1H), 7.92-8.00 (m, 2H), 8.00-8.06 (m,2H), 8.60 (s, 1H). 41-I

(R)-4-methyl- 5-(4-((1- (6-methyl- pyrazin-2-yl)- 1H-pyrazol- 4-yl)methyl) morpholin- 2-yl) isobenzofuran- 406.2 A: 0.87, 99.10% B: 1.44,98.50% XVIII: 20.05, 100% ee 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.84-1.97(m, 1H), 2.25 (s, 3H), 2.45 (s, 3H), 2.76-2.85 (m, 2H), 2.90-2.98 (m,1H), 3.58 (s, 2H), 3.72-3.84 (m, 1H), 3.96-4.03 (m, 1H), 4.78-4.87 (m,1H), 5.39 (d, J = 4.89 Hz, 2H), 7.65 (d, J = 14.92 Hz, 2H), 7.85 (s,1H), 8.47- 8.52 (m, 2H), 8.99 (s, 1H). 1(3H)-one 42-I

(R)-5-(4- ((2-(4-methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)morpholino) methyl)-1H- pyrazol-1-yl) nicotinonitrile 416.2 A: 0.86,93.10% B: 1.50, 97.10% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87-2.01 (m,1H), 2.22-2.29 (m, 4H), 2.82 (br. s., 1H), 2.94 (d, J = 11.04 Hz, 1H),3.55 (s, 2H), 3.77 (dd, J = 11.55, 9.04 Hz, 1H), 4.01 (d, J = 9.54 Hz,1H), 4.82 (d, J = 8.03 Hz, 1H), 5.34-5.42 (m, 2H), 7.59-7.74 (m, 2H),7.84 (s, 1H), 8.62 (s, 1H), 8.71-8.78 (m, 1H), 8.93 (d, J = 1.51 Hz,1H), 9.38 (d, J = 2.51 Hz, 1H). 43-I

(R)-3-(4- ((2-(4-methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)morpholino) methyl)-1H- pyrazol-1-yl) benzonitrile 415.2 A: 1.02,97.60%, B: 1.57, 96.70% XVIII: 11.61, 100% ee ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.88 (s, 1H), 2.22-2.28 (m, 3H), 2.83 (d, J = 11.55 Hz, 1H), 2.94(d, J = 10.54 Hz, 1H), 3.53 (s, 2H) 3.77 (dd, J = 11.29, 9.29 Hz, 2H),4.01 (d, J = 9.54 Hz, 1H), 4.82 (d, J = 8.03 Hz, 1H), 5.39 (d, J = 4.52Hz, 2H), 7.59-7.78 (m, 5H), 8.19 (dt, J = 8.03, 1.76 Hz, 1H), 8.31 (d, J= 1.51 Hz, 1H), 8.57 (s, 1H). 44-I

(R)-4-methyl- 5-(4-((1- (pyridin-4- yl)-1H- pyrazol-4-yl) methyl)morpholin- 2-yl) iso- benzofuran- 391.2 A: 0.54, 99.20% B: 1.18, 98.9%¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.88-1.96 (m, 1H), 2.24 (s, 4H), 2.82(d, J = 11.04 Hz, 1H), 2.93 (d, J = 11.55 Hz, 1H), 3.53 (s, 2H), 3.72-3.80 (m, 1H), 4.00 (dd, J = 11.29, 1.76 Hz, 1H), 4.82 (dd, J = 10.04,2.51 Hz, 1H), 5.38 (d, J = 4.52 Hz, 2H), 7.65-7.69 (m, 2H), 7.80 (s,1H), 7.85 (s, 2H), 8.63 (s, 3H). 1(3H)-one 45-I

(R)-4-methyl- 5-(4-((1- (4-(methyl- sulfonyl) phenyl)-1H- pyrazol-4-yl)methyl) morpholin-2- yl)isobenzo- furan-1 (3H)-one 468.2 A: 0.86,99.30%, B: 1.32, 97.80% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87-2.01 (m,1H), 2.22-2.29 (m, 3H), 2.34 (dt, J = 3.76, 1.63 Hz, 1H), 2.82 (br s.,1H), 2.94 (d, J = 11.04 Hz, 1H), 3.21 (s, 3H), 3.55 (s, 2H), 3.77 (dd, J= 11.55, 9.04 Hz, 1H), 4.01 (d, J = 9.54 Hz, 1H), 4.82 (d, J = 8.03 Hz,1H), 5.34-5.42 (m, 2H), 7.52 (s, 1H), 7.54-7.67 (m, 6H), 8.22 (s, 1H).46-I

(R)-2-methyl- 4-(4-((2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) methyl)-1H- pyrazol-1-yl) benzonitrile 429.2 A: 1.09,98.60% B: 1.68, 98.20% XVIII: 13 100% tv ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.87-1.97 (m, 1H), 2.24 (s, 4H), 2.55 (s, 3H), 2.82 (d, J = 11.55 Hz,1H), 2.92 (d, J = 11.55 Hz, 1H), 3.52 (br. s., 2H), 3.76 (t, y = 11.04Hz, 1H), 4.00 (d, J = 10.04 Hz, 1H), 4.81 (d, J = 9.04 Hz, 1H), 5.38 (d,J = 4.52 Hz, 2H), 7.59-7.69 (m, 2H), 7.92 (s, 1H), 8.51-8.59 (m, 3H),9.19 (s, 1H). 47-I

(R)-3- methyl-4- (4-((2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl)morpholino) methyl)-1H- pyrazol-1-yl) benzonitrile 429.2 A: 1.01,97.80% B: 1.56, 99.10% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (t, J =11.04 Hz, 1H), 2.24 (s, 4H), 2.33 (s, 3H), 2.83 (d, J = 11.04 Hz, 1H),2.94 (d, J = 11.04 Hz, 1H), 3.53 (s, 2H), 3.76 (td, J = 11.29, 2.51 Hz,1H), 4.00 (dd, J = 11.04, 2.01 Hz, 1H), 4.81 (dd, J = 10.04, 2.01 Hz,1H), 5.39 (d, J = 4.02 Hz, 2H), 7.56-7.64 (m, 2H), 7.65-7.70 (m, 1H),7.73 (s, 1H), 7.81 (dd, J = 8.03, 1.51 Hz, 1H), 7.92 (d, J = 1.51 Hz,1H), 8.10 (s, 1H). 48-I

(R)-5-(4-((2- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)morpholino) methyl)-1H- pyrazol-1-yl) picolinonitrile 416.2 A: 0.89,94.50% B: 1.39, 94.60% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.85-1.99 (m,1H), 2.24 (s, 4H), 2.83 (d, J = 11.55 Hz, 1H), 2.94 (d, J = 11.55 Hz,1H), 3.54 (s, 2H), 3.70-3 .83 (m, 1H), 4.00 (d, J = 11.04 Hz, 1H), 4.82(dd, J = 10.04, 2.01 Hz, 1H), 5.38 (d, J = 5.52 Hz, 2H), 7.57-7.71 (m,2H), 7.87 (s, 1H), 8.17 (d, J = 9.04 Hz, 1H), 8.43 (dd, J = 8.53, 2.51Hz, 1H), 8.69 (s, 1H), 9.28 (d, J = 2.01 Hz, 1H). 49-I

(R)-2- methoxy- 4-(4- ((2-(4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl) morpholino) methyl)-1H- pyrazol-1-yl) benzonitrile 445.1 A: 1.32,97.40% B: 1.83, 97.60% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.85-1.99 (m,1H), 2.24 (s, 4H), 2.83 (d, J = 11.55 Hz, 1H), 2.94 (d, J = 11.55 Hz,1H), 3.54 (s, 2H), 3.70-3.83 (m, 1H), 4.00-4.05 (m, 4H), 4.82 (br. s.,1H), 5.39 (d, J = 4.02 Hz, 2H), 7.53-7.70 (m, 4H), 7.78-7.84 (m, 2H),8.78 (s, 1H). 50-I

(R)-4-methyl- 5-(4-((1- (pyrazolo [1,5-a] pyrimidin- 5-yl)-1H- pyrazol-4-yl) methyl) morpholin- 2-yl) isobenzo- 431.2 A: 0.08, 98.80% B: 1.41,99.30% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87- 1.98 (m, 1H), 2.24 (s, 4H),2.82 (d, J = 11.04 Hz, 1H), 2.94 (d, J = 11.55 Hz, 1H), 3.58 (s, 2H),3.77 (td, J = 11.42, 2.26 Hz, 1H), 3.95-4.05 (m, 1H), 4.83 (dd, J =9.79, 2.26 Hz, 1H), 5.34-5.44 (m, 2H), 6.56- 6.64 (m, 1H), 7.50-7.73 (m,3H), 7.88 (s, 1H), 8.22 (d, J = 2.51 Hz, 1H), 8.60 (s, 1H), 9.19 (dd, J= 7.53, 1.00 Hz, 1H). furan- 1(3H)-one 51-I

(R)-3- methoxy-4- (4-((2-(4- methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl) morpholino) methyl)-1H- pyrazol-1-yl) benzonitrile 445.2 A: 1.03,98.40% B: 1.59, 99.40% XVIII: 12.11, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 1.86-1.94 (m, 1H), 2.22-2.28 (m, 4H), 2.81 (d, J = 12.05 Hz, 1H),2.92 (d, J = 11.55 Hz, 1H), 3.53 (s, 2H), 3.72-3.79 (m, 1H), 3.98 (d, J= 2.01 Hz, 1H), 4.00 (br. s., 3H), 4.81 (dd, J = 10.04, 2.01 Hz, 1H),5.38 (d, J = 3.51 Hz, 2H), 7.55 (dd, J = 8.28, 1.76 Hz, 1H), 7.60-7.63(m, 1H), 7.65-7.69 (m, 1H), 7.73 (s, 1H), 7.76 (d, J = 1.51 Hz, 1H),7.90 (d, J = 8.53 Hz, 1H), 8.28 (s, 1H). 52-I

(R)-4- methyl-6-(3- methyl-4- ((2-(4-methyl- 1-oxo-1,3- dihydroiso-benzofuran- 5-yl) morpholino) methyl)-1H- pyrazol-1-yl) nicotinonitrile444.1 A: 1.26, 100% B: 2.13, 98.47% XIV: 10.49, 99.69% ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.94 (s, 2H) 2.23 (s, 3H) 2.32 (s, 3H) 2.56 (s, 3H)2.77-2.84 (m, 1H) 2.89 (s, 1H) 3.49 (s, 2H) 3.75 (d, J = 1.71 Hz, 1H)3.96-4.03 (m, 1H) 4.80 (d, J = 8.31 Hz, 1H) 5.38 (d, J = 3.91 Hz, 2H)7.60- 7.64 (m, 1H) 7.66-7.70 (m, 1H) 7.91 (s, 1H) 8.45 (s, 1H) 8.79 (s,1H). 53-I

(R)-4-methyl- 6-(3-((2- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl) morpholino) methyl)-1H- pyrazol-1-yl) nicotinonitrile 430.2. A:1.17, 100% B: 2.04, 95.89% XVIII: 11.72, 100% ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.98-2.08 (m, 1H) 2.23 (s, 3H) 2.28- 2.36 (m, 1H) 2.59 (s, 3H)2.75-2.82 (m, 1H) 2.88-2.94 (m, 1H) 3.56-3.68 (m, 1H) 3.90-3.97 (m, 1H)4.00-4.19 (m, 2H) 4.64-4.73 (m, 1H) 5.39 (d, J = 6.11 Hz, 2H) 6.60 (s,1H) 7.61 (s, 1H) 7.65-7.71 (m, 1H)7.81 (d, J = 1.71 Hz, 1H) 7.99 (s, 1H)8.87 (s, 1H). 2-II

(S)-4-methyl- 6-(4-((3- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl)piperazin- 1-yl) methyl)-1H- pyrazol-1-yl) nicotinonitrile 429.2 E:10.23, 99.23% G: 11.07, 99.52% II: 3.56 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.79 (t, J = 10.29 Hz, 1H), 2.03-2.18 (m, 1H), 2.25 (s,3H), 2.66-2.67 (m, 4H), 2.79 (t, J = 9.04 Hz, 2H), 2.84-2.92 (m, 1H),2.94-3.05 (m, 1H), 3.45-3.59 (m, 2H), 4.06 (d, J = 9.54 Hz, 1H), 5.36(d, J = 1.51 Hz, 2H), 7.63 (d, J = 8.03 Hz, 1H), 7.76 (d, J = 8.03 Hz,1H), 7.85 (s, 1H), 7.98 (s, 1H), 8.52 (s, 1H), 8.82 (s, 1H). 54-I

(R)-5-(5- methoxy-4- ((3-(4- methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl) piperazin- 1-yl) methyl)-1H- pyrazol-1- yl)-3-methyl- benzo[d]490.1 A: 1.19, 98.00% B: 1.55, 98.47% XVIII: 14.42, 100% ee ¹H NMR (400MHz, CDCl₃) δ ppm 2.37 (s, 3H), 2.72-2.79 (m, 1H), 2.95-3.04 (m, 2H),3.33-3.39 (m, 1H), 3.46 (s, 3H), 3.47-3.50 (m, 1H), 3.51-3.60 (m, 2H),3.89-3.96 (m, 1H), 4.03 (s, 3H), 4.19-4.25 (m, 1H), 4.72-4.77 (m, 1H),5.27 (s, 2H), 7.22-7.25 (m, 2H), 7.32- 7.36 (m, 1H), 7.81 (d, J = 6.50Hz, 2H), 8.05 (s, 1H). oxazol- 2(3H)-one 55-I

(R)-7-fluoro- 3-methyl- 5-(4-((3-(4- methyl-1- oxo-1,3- dihydroiso-benzofuran- 5-yl) piperazin- 1-yl)methyl)- 1H- pyrazol-1-yl) 478.0 A:1.18, 98.05% B: 1.52, 98.34% XI: 13.14, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.75-1.85 (m, 1H), 2.05-2.15 (m, 1H), 2.26 (s, 3H),2.75-3.01 (m, 4H), 3.39 (s, 3H), 3.49 (s, 2H), 4.10 (d, J = 9.54 Hz,1H), 5.37 (s, 2H), 7.57-7.70 (m, 4H), 7.78 (d, J = 7.83 Hz, 1H), 8.46(s, 1H), (Exchangeable proton not observed). benzo[d] oxazol- 2(3H)-one56-I

(R)-7- methoxy-3- methyl-5-(4- ((3-(4-methyl- 1-oxo-1,3- dihydroiso-benzofuran- 5-yl) piperazin-1- yl)methyl)- 1H- 490.2 A: 0.90, 92.18% B:1.20, 95.48% XX: 10.23, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.79-1.91 (m, 1H), 2.12-2.20 (m, 1H), 2.27 (s, 3H), 2.86-3.04 (m, 4H),3.35 (s, 3H), 3.51 (br. s., 2H), 3.96 (s, 3H), 4.16 (br. s., 1H), 5.38(d, J = 2.20 Hz, 2H), 7.31 (d, J = 1.96 Hz, 1H), 7.39 (d, J = 1.96 Hz,1H), 7.64-7.70 (m, 2H), 7.78 (d, J = 8.07 Hz, 1H), 8.47 (s, 1H),(Exchangeable proton not observed). pyrazol-1-yl) benzo[d] oxazol-2(3H)-one 57-I

(R)-3,7- dimethyl-5- (4-((3-(4- methyl-1- oxo-1,3- dihydroiso-benzofuran- 5-yl) piperazin-1-yl) methyl)-1H- pyrazol- 1-yl)benzo[d]oxazol-2 474.1 A: 1.61, 97.04% B: 1.49, 98.74% XIV: 9.11 100% ee ¹HNMR (400 MHz, CD₃OD) δ ppm 2.42 (s, 3H), 2.44 (s, 3H), 2.65-2.78 (m,2H), 3.45 (s, 3H), 3.45-3.58 (m, 4H), 3.89 (s, 2H), 4.77 (d, J = 2.51Hz, 1H), 5.42 (s, 2H), 7.38 (d, J = 1.51 Hz, 1H), 7.41 (d, J = 2.01 Hz,1H), 7.72 (d, J = 8.03 Hz, 1H), 7.76 (s, 1H), 7.85 (d, J = 8.03 Hz, 1H),8.28 (s, 1H), (Exchangeable proton not observed). (3H)-one 58-I

(R)-3- methyl-5- (4-((3-(4- methyl-1-oxo- 1,3- dihydroiso- benzofuran-5-yl) piperazin-1- yl)methyl)- 1H-pyrazol-1- 460.0 A: 1.08, 95.95% B:1.38, 95.74% V: 9.53, 92.68% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (s,1H), 2.17 (s, 1H), 2.27 (s, 3H), 2.87 (br. s., 2H), 2.98 (br. s., 1H),3.06 (br. s., 1H), 3.38 (s, 3H), 3.52 (br. s., 2H), 4.19 (br. s., 1H),5.38 (d, J = 2.45 Hz, 2H), 7.41 (d, J = 8.56 Hz, 1H), 7.57 (dd, J =8.68, 2.32 Hz, 1H), 7.63-7.71 (m, 2H), 7.72-7.80 (m, 2H), 8.42 (s, 1H),(Exchangeable proton not observed). yl) benzo[d] oxazol-2(3H)- one 59-I

(R)-4- methoxy- 6-(4- ((3-(4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl) piperazin-1-yl) methyl)-1H- pyrazol-1- 445.1 A: 1.15, 98.35% B:1.51, 98.43% V: 8.30, 98.31% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.93(br. s., 1H), 2.20 (br. s., 1H), 2.27 (s, 3H), 2.85 (br. s., 2H),2.95-3.12 (m, 2H), 3.56 (br. s., 2H), 4.10 (s, 3H), 4.20 (br. s., 1H),5.30-5.47 (m, 3H), 7.60 (s, 1H), 7.65-7.72 (m, 1H), 7.73-7.81 (m, 1H),7.87 (s, 1H), 8.54 (s, 1H), 8.73 (s, 1H). yl)nicotino- nitrile 61-I

(R)-3-methyl- 5-(4-((3- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl)piperazin- 1-yl) methyl)-1H- 1,2,3-triazol- 1-yl)benzo [d]oxazol-461.0 A: 1.07, 96.74% B: 1.24, 98.65% V: 8.68, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.02 (br. s., 1H), 2.28 (s, 3H), 2.33 (s, 1H), 2.67 (s,1H), 2.90 (d, J = 11.74 Hz, 2H), 2.98 (br. s., 1H), 3.08 (d, J = 11.00Hz, 1H), 3.40 (s, 3H), 3.74 (s, 2H), 4.19 (br. s., 1H), 5.33-5.44 (m,2H), 7.52 (d, J = 8.56 Hz, 1H), 7.63-7.71 (m, 2H), 7.78 (d, J = 7.83 Hz,1H), 7.88 (d, J = 1.96 Hz, 1H), (Exchangeable proton not observed).2(3H)-one 62-I

(R)-6-(5- ((3-(4- methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)piperazin- 1-yl) methyl)- 1,3,4- oxadiazol- 417.0 A: 0.99, 100% B: 1.14,98.88% XX: 8.88, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.04 (t, J =10.27 Hz, 1H), 2.29 (s, 3H), 2.33 (d, J = 1.96 Hz, 1H), 2.80-2.94 (m,3H), 3.00 (d, J = 11.74 Hz, 1H), 4.00 (s, 2H), 4.09 (d, J = 10.03 Hz,1H), 5.38 (s, 2H), 7.65 (d, J = 7.83 Hz, 1H), 7.76 (d, J = 7.83 Hz, 1H),8.35 (d, J = 8.31 Hz, 1H), 8.57 (dd, J = 8.19, 2.08 Hz, 1H), 9.22 (d, J= 2.20 Hz, 1H), (Exchangeable proton not observed). 2-yl) nicotino-nitrile 63-I

(R)-4- methoxy- 5′-((3-(4- methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl) piperazin-1- yl) 456.1 A: 1.23, 100% B: 1.63, 100% VIII: 13.51,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (br. s., 1H), 2.16-2.20 (brs, 1H), 2.20 (s, 3H), 2.80 (t, J = 11.13 Hz, 2H), 2.87-3.10 (m, 2H),3.53-3.76 (m, 2H), 4.12 (s, 3H), 4.12-4.19 (br.s, 1H), 5.26- 5.43 (m,2H), 7.66 (d, J = 7.58 Hz, 1H), 7.78 (d, J = 7.83 Hz, 1H), 7.96 (dd, J =8.31, 1.96 Hz, 1H), 8.15 (s, 1H), 8.41 (d, J = 8.07 Hz, 1H), 8.68 (s,1H), 8.91 (s, 1H), (Exchangeable proton not observed). methyl)- [2,2′-bipyridine]- 5-carbonitrile 64-I

(R)-1-(5- ((3-(4- methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)piperazin-1- 415.1 A: 1.19, 100% B: 1.54, 100% IV: 14.93, 99.42% ee ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.85 (t, J = 10.39 Hz, 1H), 2.15 (d, J =10.76 Hz, 1H), 2.22 (s, 3H), 2.64-2.84 (m, 2H), 2.86-3.04 (m, 2H),3.54-3 .68 (m, 2H), 4.08 (d, J = 10.76 Hz, 1H), 5.36 (d, J = 2.20 Hz,2H), 7.64 (d, J = 8.07 Hz, 1H), 7.77 (d, J = 8.07 Hz, 1H), 7.90-7.97 (m,1H), 7.99-8.07 (m, 1H), yl)methyl) 8.37-8.48 (m, 2H), 9.39 (s, 1H),pyridin-2-yl)- (Exchangeable proton not observed). 1H-pyrazole-4-carbonitrile 65-I

(R)-1-(5- ((3-(4- methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)piperazin-1-yl) 415.2 A: 0.84, 98.26% B: 1.08, 98.91% IV: 15.06, 98.12%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.86 (t, J = 9.90 Hz, 1H), 2.14 (d, J= 10.76 Hz, 1H), 2.23 (s, 3H), 2.76 (t, J = 8.07 Hz, 2H), 2.90 (d, J =10.52 Hz, 1H), 2.99 (d, J = 11.00 Hz, 1H), 3.55- 3.69 (m, 2H), 4.08 (d,J = 7.83 Hz, 1H), 5.36 (d, J = 3.42 Hz, 2H), 7.65 (d, J = 8.07 Hz, 1H),7.77 (d, J = 8.07 Hz, 1H), methyl) 7.87 (d, J = 8.31 Hz, 1H), 8.02 (dd,J = pyridin-2- 8.56, 1.96 Hz, 1H), 8.47 (d, J = 1.96 Hz, yl)-1H- 1H),8.74 (d, J = 1.22 Hz, 1H), 8.91 (d, imidazole- J = 1.22 Hz, 1H),(Exchangeable proton 4-carbonitrile not observed). 66-I

(R)-4-methyl- 5-(4-((6- (4-methyl- 1H-imidazol- 1-yl)pyridin- 3-yl)methyl) piperazin-2-yl) 404.2 F: 6.15, 97.63% G: 6.93, 98.08% V: 6.36,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.84 (t, J = 9.90 Hz, 1H), 2.17(s, 4H), 2.33 (d, J = 1.71 Hz, 3H), 2.71-2.81 (m, 2H), 2.86-2.93 (m,1H), 2.99 (d, J = 11.25 Hz, 1H), 3.51-3.62 (m, 2H), 4.07 (d, J = 9.54Hz, 1H), 5.36 (s, 2H), 7.62- 7.66 (m, 2H), 7.70 (d, J = 8.31 Hz, 1H),7.77 (d, J = 8.07 Hz, 1H), 7.90 (dd, isobenzo- J = 8.19, 2.08 Hz, 1H),8.33-8.50 (m, furan-1 2H), (Exchangeable proton not observed). (3H)-one67-I

(R)-4-methyl- 5-(4-((6- (3-methyl- 1H-1,2,4- triazol-1-yl) pyridin-3-yl)methyl) piperazin-2-yl) 405.1 A: 1.01, 100% B: 1.25, 99.51% V: 6.16,96.66% ee ¹H NMR (400 MHz, DMSO-d₆) δ 1.75-1.92 (m, 1H), 2.08-2.18 (m,1H), 2.22 (s, 3H), 2.38 (s, 3H), 2.64-2.82 (m, 2H), 2.91 (d, J = 11.74Hz, 1H), 2.96-3.05 (m, 1H), 3.48-3.71 (m, 2H), 4.08 (d, J = 7.83 Hz,1H), 5.36 (s, 2H), 7.64 (d, J =8.07 Hz, 1H), 7.78 (dd, J = 8.19, 3.30Hz, 2H), 7.99 (dd, J = 8.31, isobenzo- 1.96 Hz, 1H), 8.41 (d, J = 2.20Hz, 1H), furan-1(3H)- 9.19 (s, 1H), (Exchangeable proton not oneobserved). 68-I

(R)-6-(4- ((4-acetyl-3- (4-methyl-1- oxo-1,3-di- hydroiso- benzofuran-5-yl)piperazin- 1-yl) methyl)-1H- pyrazol-1-yl)- 4- 471.1 A: 1.16, 100%B: 1.77, 100% X: 9.45, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.05 (d,J = 13.69 Hz, 3H), 2.13-2.31 (m, 4H), 2.40 (br s., 1H), 2.57 (s, 3H),2.91-3.15 (m, 2H), 3.46-3.66 (m, 3H), 3.72 (br s., 1H), 5.15-5.42 (m,2H), 5.72 (br. s., 1H), 7.68 (d, J = 8.07 Hz, 1H), 7.81 (br. s., 1H),7.96 (s, 1H), 8.06- 8.51 (m, 2H), 8.78 (s, 1H). methyl- nicotino-nitrile 69-I

(R)-4-methyl- 6-(4-((3- (4-methyl-1- oxo-1,3- dihydroisob- enzofuran-5-yl)-4-(methyl- sulfonyl) piperazin-1- yl)methyl)- 1H-pyrazol- 507.0 A:1.27, 100% B: 1.85, 100% XIX: 11.31, 87.54% ee ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.07 (s, 1H), 2.28 (s, 3H), 2.45 (dd, J = 11.37, 5.75 Hz, 1H),2.55-2.69 (m, 3H), 2.73- 2.84 (m, 4H), 2.90 (d, J = 10.76 Hz, 1H),3.44-3.51 (m, 1H), 3.53-3.65 (m, 3H), 5.15 (t, J = 3.67 Hz, 1H),5.25-5.34 (m, 1H), 5.37-5.47 (m, 1H), 7.71 (d, J = 8.07 Hz, 1H), 7.76(s, 1H), 7.95 (s. 1H), 8.15 (d, J = 8.07 Hz, 1H), 8.40 (s, 1H), 8.79 (s,1H). 1-yl) nicotino- nitrile 70-I

(R)-4- methyl-6- (4-((4- methyl-3- (4-methyl-1- oxo-1,3- dihydroiso-benzofuran-5- yl)piperazin- 1-yl)methyl)- 1H- 443.0 F: 5.36, 95.73% XX:6.21, 95.67% X: 4.82, 91.28% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.88(br. s., 1H), 1.94 (s, 3H), 2.26 (br. s., 4H), 2.30-2.35 (m, 1H), 2.57(s, 3H), 2.71 (d, J = 10.54 Hz, 1H), 2.81- 2.97 (m, 2H), 3.41-3.47 (m,1H), 3.50 (s, 2H), 5.30-5.43 (m, 2H), 7.65 (s, 2H), 7.84 (s, 1H), 7.98(s, 1H), 8.52 (s, 1H), 8.83 (s, 1H). pyrazol-1-yl) nicotino- nitrile71-I

(R)-3-methyl- 5-(4-((3- (4-methyl-1- oxo-1,3- dihydroiso- benzofuran-5-yl)-5-oxo- piperazin-1- yl)methyl)- 1H- pyrazol-1-yl) benzo[d] 474.0 A:1.09, 97.66% B: 1.32, 94.12% IV: 6.81, 100% ee ¹H NMR (400 MHz, DMSO-d₆)δ 2.22 (s, 3H), 2.33-2.44 (m, 1H), 2.94 (dd, J = 11.98, 4.40 Hz, 1H),3.14 (s, 2H), 3.39 (s, 3H), 3.47-3.63 (m, 2H), 4.95 (br. s., 1H), 5.29(s, 1H), 5.36-5.45 (m, 1H), 7.39 (d, J = 8.80 Hz, 1H), 7.44-7.52 (m,1H), 7.54-7.63 (m, 2H), 7.67-7.77 (m, 2H), 8.16 (s, 1H), 8.21 (s, 1H).oxazol- 2(3H)-one 72-I

(R)-3-methyl- 5-(4-((3- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl)-5- oxo- piperazin-1- yl)methyl)- 1H-1,2,3- triazol-1-yl) 475.0 A:1.21, 97.22% B: 1.12, 100% V: 13.58, 88% ee ¹H NMR (400 MHz, DMSO-d₆) δ2.25 (s, 3H), 2.43 (dd, J = 11.74, 6.60 Hz, 1H), 3.04 (dd, J = 12.10,4.77 Hz, 1H), 3.21 (s, 2H), 3.40 (s, 3H), 3.78 (s, 2H), 4.96 (br. s.,1H), 5.23-5.42 (m, 2H), 7.46-7.59 (m, 3H), 7.72 (d, J = 8.07 Hz, 1H),7.82 (d, J = 1.96 Hz, 1H), 8.17 (s, 1H), 8.45 (s, 1H). benzo[d] oxazol-2(3H)-one 73-I

(R)-1-(5- ((3-(4- methyl- 1-oxo-1,3- dihydroiso- benzofuran- 5-yl)-5-oxopiperazin- 430.1 A: 1.35, 100% B: 1.43, 100% XIV: 8.05, 91.59% ee ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.22 (s, 3H), 3.01 (d, J = 9.78 Hz, 1H),3.11-3.25 (m, 3H), 3.76 (br. s., 2H), 4.98 (br. s., 1H), 5.38 (qJ =15.65 Hz, 2H), 7.58 (d, J = 7.83 Hz, 1H), 7.74 (d, J = 8.07 Hz, 1H),7.83-7.90 (m, 1H), 7.91-7.97 (m, 1H), 8.25 (s, 1H), 8.42 (s, 1H), 9.69(s, 1H). 1-yl) methyl) pyridin-2-yl)- 1H-1,2, 4-triazole-3- carbonitrile74-I

(R)-4- methoxy-5′- ((3- (4-methyl- 1-oxo-1,3-di- hydroiso- benzofuran-5-yl)-5-oxo- piperazin-1- yl)methyl)- 470.1 A: 1.32, 94.19% B: 1.51,94.93% XVIII: 14.74, 95.27% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.17 (s,3H), 2.41-2.45 (m, 1H), 2.91- 2.94 (m, 1H), 3.16 (q, J = 16.30 Hz, 2H),3.57-3.76 (m, 2H), 4.13 (s, 3H), 4.96 (br. s., 1H), 5.20-5.31 (m, 1H),5.33-5.43 (m, 1H), 7.58 (d, J = 8.07 Hz, 1H), 7.70-7.80 (m, 2H), 8.11(s, 1H), 8.22 (s, 1H), 8.31 (d, J = 8.07 Hz, 1H), 8.46 (s, 1H), 8.91 (s,1H). [2,2′- bipyridine]- 5-carbonitrile 75-I

(R)-6-(4- methyl-1-oxo- 1,3- dihydroiso- benzofuran-5- yl)-4-((6-(3-methyl- 1H-1,2,4- 419.1 A: 1.06, 100% B: 1.18, 100% XIV: 7.21, 94.14% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H), 2.38 (s, 3H),2.41-2.44 (m, 1H), 2.93-2.96 (m, 1H), 3.05-3.19 (m, 2H), 3.65 (s, 2H),4.96 (br. s., 1H), 5.29-5.46 (m, 2H), 7.58 (d, J = 8.07 Hz, 1H), 7.72(dd, J = 15.77, 8.19 Hz, 2H), 7.82 (dd, J = 8.44, 2.08 Hz, 1H), 8.21 (s,1H), 8.30 (d, J = 1.96 Hz, 1H), 9.17 (s, triazol- 1H). 1-yl)pyridin-3-yl) methyl) piperazin-2- one 76-I

(R)-6-(4- methyl-1- oxo-1,3- dihydroiso- benzo- furan-5-yl)- 4-((6-(4-methyl-1H- 418.0 A: 0.90, 100% B: 1.21, 100% IV: 13.83, 94.47% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.16 (s, 3H), 2.20 (s, 3H), 2.44 (dd, J =11.86, 6.48 Hz, 1H), 2.93 (dd, J = 11.74, 4.40 Hz, 1H), 3.03-3.19 (m,2H), 3.62 (s, 2H) 4.95 (br. s., 1H), 5.37 (q, J = 15.65 Hz, 2H), 7.57(d, J = 8.07 Hz, 1H), 7.60-7.66 (m, 2H), 7.67-7.76 (m, 2H), 8.20 (s,1H), 8.25 (s, 1H), 8.37 (s, imidazol- 1H). 1-yl)pyridin- 3-yl)methyl)piperazin- 2-one 77-I

(R)-4- methyl-6- (4-((4- methyl-3- (4-methyl-1- oxo-1,3- dihydroiso-benzofuran- 5-yl)-5- oxo- piperazin-1- 457.2 A: 1.15, 97.87% B: 1.39,99.90% XI: 9.28, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H),2.56 (s, 3H), 2.65 (s, 4H), 2.67-2.69 (m, 1H), 2.86-2.90 (m, 1H),3.07-3.12 (m, 1H), 3.31-3.57 (m, 2H), 4.97 (t, J = 4.0 Hz, 1H),5.25-5.29 (m, 1H), 5.39-5.43 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.60 (s,1H), 7.76 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 8.09 (s, 1H), 8.72 (s, 1H).yl)methyl)- 1H-pyrazol- 1-yl) nicotino- nitrile 78-I

(R)-4- methoxy-6-(4- ((5-(4- methyl-1- oxo-1,3- dihydroiso- benzofura5-yl)-2- oxo- oxazolidin- 3-yl)methyl)- 446.0 A: 1.45, 95.92% B: 1.31,95.39% III: 18.26, 91.42% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.24 (s,3H), 3.33-3.38 (m, 1H), 4.11 (s, 3H), 4.10-4.14 (m, 2H), 4.31-4.35 (m,1H), 5.41 (d, J = 7.03 Hz, 2H), 5.94- 6.01 (m, 1H), 7.57 (d, J = 8.01Hz, 1H), 7.60 (s, 1H), 7.75 (d, J = 7.95 Hz, 1H), 8.04 (s, 1H), 8.64 (s,1H), 8.75 (s, 1H). 1H- imidazol- 1-yl) nicotino- nitrile 79-I

(R)-6-(5- methoxy-4- ((5-(4- methyl-1-oxo- 1,3-dihydroiso- benzofuran-5-yl)-2- oxo- oxazolidin- 3-yl) methyl)-1H- 460.1 A: 2.19, 100% B: 2.19,100% XVIII: 9.18, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (s, 3H),2.55 (s, 3H), 3.23-3.28 (m, 1H), 3.95 (s, 3H), 4.04-4.08 (m, 1H), 4.28(d, J = 6.85 Hz, 2H), 5.40 (d, J = 7.58 Hz, 2H), 5.92-5.98 (m, 1H), 7.55(d, J = 8.0 Hz, 1H), 7.73-7.78 (m, 2H), 8.50 (s, 1H), 8.76 (s, 1H).pyrazol- 1-yl)-4- methyl- nicotino- nitrile 80-I

(R)-3-methyl- 5-(4-((5- (4-methyl- 1-oxo-1,3- dihydroiso- benzofuran-5-yl)-2-oxo- oxazolidin- 3-yl)methyl)- 1H- pyrazol-1-yl) 461.1 A: 1.50,98.39% B: 1.48, 98.56% V: 13.40, 97.89% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 2.23, (s, 3H), 3.39 (s, 3H), 4.05-4.12 (m, 2H), 4.38 (d, J = 19.56Hz, 2H), 5.40 (d, J = 7.58 Hz, 2H), 5.92-6.01 (m, 1H), 7.43 (s, 1H),7.51-7.59 (m, 2H), 7.69-7.79 (m, 3H), 8.48 (s, 1H). benzo[d] oxazol-2(3H)-one

Example 81-I:6-(4-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Example 81-I was prepared (0.130 g, 30.10%) as an off-white solid, byusing a similar synthetic protocol as that of Example 1-I and startingfrom Intermediate 38-I (0.35 g, 1.32 mmol) and Intermediate 6 (0.20 g,0.94 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.73 (dt, J=15.90, 10.15 Hz,2H), 2.26 (s, 3H), 2.57 (s, 3H), 2.82 (d, J=10.03 Hz, 1H), 2.88-3.02 (m,2H), 3.37-3.43 (m, 2H), 3.53 (s, 2H), 4.17 (d, J=8.07 Hz, 1H), 4.61 (br.s., 1H), 5.37 (s, 2H), 7.64 (d, J=8.07 Hz, 1H), 7.78 (d, J=8.07 Hz, 1H),7.84 (s, 1H), 7.98 (s, 1H), 8.51 (s, 1H), 8.82 (s, 1H), (1 Exchangeableproton not observed). HPLC (Method-U): retention time 4.78 min, purity:99.33%, (Method-7): retention time 4.90 min, purity: 98.18%, LCMS(Method D): retention time 1.66 min, [M+H] 459.2. Chiral purity(Method-XIX): retention time 11.50 min, 100% ee.

Example 82-I:6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Example 82-I was prepared (0.25 g, 46.60%) as an off-white solid, byusing a similar synthetic protocol as that of Example 1-I and startingfrom Intermediate 40-I (0.30 g, 0.117 mmol) and Intermediate 28 (0.25 g,0.117 mmol). ¹H NMR (400 MHz, DMSO-d6) δ 1.07 (s, 3H), 1.32 (s, 3H),1.83 (t, J=10.1 Hz, 1H), 1.92 (d, J=10.3 Hz, 1H), 2.06 (br. s., 1H),2.29 (s, 3H), 2.57 (d, J=10.0 Hz, 1H), 2.62 (s, 3H), 2.88 (d, J=8.6 Hz,1H), 3.79-3.70 (m, 2H), 4.41 (d, J=8.8 Hz, 1H), 5.39 (s, 2H), 7.66 (d,J=8.1 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 8.94(s, 1H). HPLC (Method-U): retention time 4.84 min, purity: 96.03%,(Method-T): retention time 6.27 min, purity: 97.15%, LCMS (Method-D):retention time 2.15 min, [M+H] 458.4. Chiral purity (Method-XV):retention time 4.60 min, 100% ee. SOR: [α]²⁵ _(D)=−30.00 (c 0.1, DMSO).

Example 83-I:4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile

Example 83-I was prepared (0.045 g, 20.41%), by using a similarsynthetic protocol as that of Example 1-I and starting from Intermediate51-I (0.12 g, 0.49 mmol) and Intermediate 28 (0.102 g, 0.49 mmol). ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=5.9 Hz, 3H), 1.80 (br. s., 2H),2.27 (s, 3H), 2.64 (s, 3H), 2.84 (br. s., 2H), 2.96 (br. s., 1H), 3.75(s, 2H), 4.15 (br. s., 1H), 5.45-5.30 (m, 2H), 7.64 (d, J=8.0 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.20 (s, 1H), 8.92 (s, 1H), (1Exchangeable proton not observed). HPLC (Method-U): retention time 6.50min, purity: 97.70%. (Method-T): retention time 7.53 min, purity:98.10%. LCMS (Method-J): retention time 1.86 min, [M+H] 444.2, purity:99.60%. Chiral purity (Method-MV): retention time 7.27 min, 100% ee.

Example 84-I:6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Example 84-I was prepared (0.02 g, 20.68%), by using a similar syntheticprotocol as that of Example 1-I and starting from Intermediate 52-I(0.05 g, 0.49 mmol) and Intermediate 30 (0.04 g, 0.49 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.62 (d, J=6.8 Hz, 1H), 1.92 (d, J=10.5 Hz, 1H),2.18-2.06 (m, 1H), 2.25 (s, 4H), 2.67-2.60 (m, 3H), 2.80 (d, J=10.0 Hz,1H), 2.94 (br. s., 1H), 3.07 (br. s., 1H), 3.75 (br. s., 3H), 4.56 (d,J=5.1 Hz, 1H), 5.46-5.26 (m, 2H), 7.53 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8Hz, 1H), 8.28 (s, 1H), 8.77 (s, 1H), 8.98 (s, 1H). LCMS/HPLC (Method-R):retention time 0.89 min, [M+H] 445.2, purity: 95.00%, (Method-S):retention time 1.20 min, [M+H] 445.2, purity: 100%. Chiral purity(Method-XVIII): retention time 14.30 min, 98.40% ee.

The examples in Table 2 were synthesized using procedures in Example 1-Ito 24-I and 81-I to 84-I.

HPLC/ LCMS Method: RT LCMS (min.), Example Structure Name (M + H)⁺Purity NMR 85-I

2,4-dimethyl-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-2H- 1,2,3-triazol-2-yl)nicotinonitrile 458.3 S: 1.50, 96.42% R: 1.15, 96.95% V: 7.33, 98.50%ee ¹H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J = 5.9 Hz, 3 H), 1.84 (br. s.,2 H), 2.24-2.31 (m, 3 H), 2.60 (s, 3 H), 2.69-2.74 (m, 3 H), 2.77- 2.88(m, 2 H), 3.00 (br. s., 1 H), 3.77 (s, 2 H), 4.20 (br. s., 1 H),5.31-5.46 (m, 2 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 1H), 7.94 (s, 1 H), 8.19 (s, 1 H), (1 Exchangeable proton not observed).86-I

4-methoxy-2- methyl-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- 1,2,3-triazol-1-yl)nicotinonitrile 474.3 S: 1.50, 94.55% R: 1.49, 99.47% XVIII: 13.27,100% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.20-1.34 (m, 3 H), 2.37 (s, 4 H),2.68 (s, 3 H), 3.18 (s, 2 H), 3.94- 3.99 (m, 2 H), 4.15 (s, 3 H), 4.78(br. s., 1 H), 5.37-5.56 (m, 2 H), 7.75 (s, 1 H), 7.78 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1 H), 8.50 (s, 1 H), 8.86 (s, 1 H), 9.44 (s, 1H), (1 Exchangeable proton not observed). 87-III

6-(4-((3- (hydroxymethyl)-5- (4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin- 1-yl)methyl)-1H- pyrazol-1-yl)-4- methylnicotinonitrile,(Enantiomer-III) 459.3 S: 1.39, 100% R: 1.15, 100% XXIV: 5.80, 100% ee¹H NMR (400 MHz, DMSO-d6) δ 1.98-2.14 (m, 1 H), 2.27 (s, 3 H), 2.41 (d,J = 10.3 Hz, 1 H), 2.58 (s, 3 H), 2.65 (d, J = 9.3 Hz, 1 H), 2.73 (d, J= 7.1 Hz, 1 H), 2.92 (d, J = 15.7 Hz, 1 H), 3.46-3.58 (m, 3 H), 3.76(br. s., 1 H), 4.40 (d, J = 5.6 Hz, 1 H), 4.58 (br. s., 1 H), 5.29-5.45(m, 2 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.87 (s, 1 H), 7.93- 8.05 (m, 2 H),8.53 (s, 1 H), 8.84 (s, H), (1 Exchangeable proton not observed). 88-III

6-(4-((3- (hydroxymethyl)-5- (4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin- 1-yl)methyl)-1H- 1,2,3-triazol-1-yl)- 4-methylnicotinonitrile, (Enantiomer-III) 460.2 S: 1.28, 100% R: 1.09,97.86% XIX: 7.63, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ 2 .02-2.17 (m, 1H), 2.27 (s, 3 H), 2.45 (br. s., 1 H), 2.63-2.69 (m, 4 H), 2.79 (d, J =9.8 Hz, 1 H), 2.91 (d, J = 12.5 Hz, 1 H), 3.53 (br. s., 1 H), 3.74 (s, 3H), 4.40 (br. s., 1 H), 4.59 (br. s., 1 H), 5.38 (d, J = 2.4 Hz, 2 H),7.64 (d, J = 8.3 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 8.30 (s, 1 H),8.79 (s, 1 H), 9.01 (s, 1 H), (1 Exchangeable proton not observed).89-III

6-(4-((3- (hydroxymethyl)-5- (4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin- 1-yl)methyl)-1H- pyrazol-1-yl)-4-methoxynicotinonitrile, (Enantiomer-III) 475.3 S: 1.34, 96.27% R: 1.11,97.98% VI: 17.65, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.99-2.11 (m, 2H), 2.21-2.31 (m, 3 H), 2.40 (dd, J = 11.1, 3.8 Hz, 1 H), 2.64 (d, J =8.1 Hz, 1 H), 2.73 (d, J = 7.6 Hz, 1 H), 2.90-2.96 (m, 1 H), 3.51 (s, 3H), 3.75 (d, J = 8.3 Hz, 1 H), 4.11 (s, 3 H), 4.36-4.43 (m, 1 H), 4.57(br. s., 1 H), 5.32- 5.42 (m, 2 H), 7.61 (s, 1 H), 7.65 (d, J = 7.8 Hz,1 H), 7.88 (s, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 8.53 (s, 1 H), 8.74 (s,1 H). 90-I

6-(4-((3- (hydroxymethyl- d2)-5-(4-methyl-1- oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- pyrazol-1-yl)-4-methylnicotinonitrile, (Enantiomer-I) 461.3 S: 1.33, 100% R: 1.05,99.36% XVIII: 14.17, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.73 (br. s., 2H), 1.92 (s, 1 H), 2.27 (s, 3 H), 2.58 (s, 3 H), 2.83 (d, J = 10.3 Hz, 1H), 2.88-3.03 (m, 2 H), 3.54 (br. s., 2 H), 4.18 (d, J = 10.0 Hz, 1 H),4.60 (br. s., 1 H), 5.30-5.49 (m, 2 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.79(d, J = 7.8 Hz, 1 H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8.53 (s, 1 H), 8.84(s, 1 H). 91-I

1-(5-(((3R,5R)-3- (hydroxymethyl)-5- (4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1- yl)methyl)pyridin-2-yl)-3-methyl-1H- pyrazole-4-carbonitrile 460.3 S: 1.13, 100% R: 0.96,100% XV: 5.55, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.80 (d, J = 10.3 Hz,2 H), 2.26 (s, 3 H), 2.42 (s, 3 H), 2.81 (d, J = 9.0 Hz, 1 H), 2.92 (d,J = 11.5 Hz, 2 H), 3.37 (br. s., 2 H), 3.65 (s, 2 H), 4.21 (br. s., 1H), 4.65 (br. s., 1 H), 5.30-5.47 (m, 2 H), 7.67 (d, J = 7.8 Hz, 1 H),7.80 (d, J = 8.3 Hz, 1 H), 8.84 (s, 2 H), 9.36 (s, 1 H), (2 Exchangeableprotons not observed). 92-I

6-(4-(((3R,4R)-4- hydroxy-3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H- pyrazol-1-yl)-2,4-dimethylnicotinonitrile 458.2 S: 1.47, 99.34% R: 1.06, 100% XXI: 3.85,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.70 (m, 1 H), 1.93 (d, J =9.78 Hz, 1 H), 1.98-2.10 (m, 1 H), 2.18 (t, J = 10.76 Hz, 1 H), 2.24 (s,3 H), 2.54 (s, 3 H), 2.66 (s, 3 H), 2.73 (d, J = 10.03 Hz, 1 H), 2.92(d, J = 12.23 Hz, 1 H), 3.01-3.12 (m, 1 H), 3.43-3.57 (m, 2 H), 3.72(br. s., 1 H), 4.56 (br. s., 1 H), 5.26-5.44 (m, 2 H), 7.52 (d, J = 8.07Hz, 1 H), 7.59-7.67 (m, 1 H), 7.82 (s, 2 H), 8.49 (s, 1 H). 93-I

2-methoxy-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- pyrazol-1-yl)nicotinonitrile 459.2 S: 1.60, 95.30% R: 1.12, 95.10% ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.05 (d, J = 5.1 Hz, 3 H), 1.76 (br. s., 2 H),2.31-2.19 (m, 3 H), 2.83 (d, J = 9.5 Hz, 2 H), 3.00 (br. s., 1 H), 3.52(s, 2 H), 4.13- 3.99 (m, 4 H), 4.17 (d, J = 9.3 Hz, 1 H), 5.49-5.26 (m,2 H), 7.56 (d, J = 8.3 Hz, 1 H), 7.64-7.66 (d, J = 8 Hz, 1 H), 7.80 (d,J = 7.8 Hz, 1H), 7.86 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.59 (s, 1H).94-I

5-((2R,6S)-4-((2- (4,5-dimethyl-1H- imidazol-1- yl)pyrimidin-5-yl)methyl)-6- methylpiperazin-2- yl)-4- methylisobenzofuran- 1(3H)-one433.3 S: 1.44, 100% R: 0.77, 98.00% XXI: 6.06 96.51% ee ¹H NMR (400 MHz,DMSO-d6) δ 1.04 (d, J = 6.1 Hz, 3 H), 1.81 (d, J = 10.3 Hz, 2 H), 2.11(s, 3 H), 2.31-2.20 (m, 3 H), 2.46 (s, 3 H), 2.80 (br. s., 3 H), 3.61(s, 2 H), 4.20 (d, J = 5.1 Hz, 1 H), 5.52- 5.30 (m, 2 H), 7.67 (d, J =7.8 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 8.31 (s, 1 H), 8.77 (s, 2 H),(1 Exchangable proton not observed). 95-I

4,6-dimethyl-2-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- imidazol-1-yl)pyrimidine-5- carbonitrile 458.2 S: 1.36, 100% R: 0.96, 100% XIX:9.54 92.65% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.23 (d, J = 10.8 Hz, 3 H),2.34 (s, 3 H), 2.70 (s, 6 H), 3.09 (br. s., 2 H), 3.69 (br. s., 4 H),4.63 (br. s., 1 H), 5.55-5.33 (m, 2H), 7.15 (br. s., 1 H), 7.80 (br. s.,2 H), 7.89 (br. s., 1 H), 8.60 (br. s., 1H), (1 Exchangeable proton notobserved). 96-I

4-methyl-2-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- pyrazol-1-yl)pyrimidine-5- carbonitrile 444.3 S: 1.21, 100% B: 0.86, 100% XVIII:14.76, 97.78% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J = 4.6 Hz, 3 H),1.76 (br. s., 2 H), 2.26 (s, 3 H), 2.69 (s, 3 H), 2.82 (br. s., 2 H),3.01 (br. s., 1 H), 3.17 (d, J = 4.9 Hz, 1 H), 3.54 (br. s., 2 H), 4.20(br. s., 1 H), 5.45-5.30 (m, 2 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.78 (d, J= 8.1 Hz, 1 H), 7.88 (s, 1 H), 8.56 (s, 1 H), 9.18 (s, 1 H). 97-I

4-methoxy-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- imidazol-1-yl)nicotinonitrile 459.3 S: 1.25, 99.45% R: 8.78, 100% ¹H NMR (400 MHz,DMSO-d6) δ 1.28 (d, J = 6.4 Hz, 3 H), 2.36 (s, 3 H), 2.63-2.55 (m, 1 H),2.81- 2.70 (m, 1 H), 3.30 (d, J = 11.0 Hz, 2 H), 3.66 (br. s., 1 H),3.92 (br. s., 3 H), 4.13 (s, 3 H), 4.79 (d, J = 12.2 Hz, 1 H), 5.57-5.35(m, 2 H), 7.66 (s, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.87 (d, J = 8.1 Hz,1 H), 8.14 (s, 1 H), 8.88-8.75 (m, 2 H). 98-I

4-methyl-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- imidazol-1-yl)nicotinonitrile 443.3 R: 0.85, 97.18% S: 1.25, 98.65% XVIII: 13.30,95.52% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J = 6.1 Hz, 3 H), 1.84(br. s., 2 H), 2.32-2.23 (m, 3 H), 2.56 (s, 3 H), 2.90-2.78 (m, 2 H),3.00 (br. s., 1 H), 3.52 (s, 2 H), 4.18 (br. s., 1 H), 5.50-5.26 (m, 2H), 7.66 (d, J = 8.1 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.86 (s, 1 H),7.99 (s, 1 H), 8.63-8.45 (m, 1 H), 8.86 (s, 1 H), (1 Exchangeable protonnot observed). 99-I

4-methoxy-2-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- pyrazol-1-yl)pyrimidine-5- carbonitrile 460.3 R: 0.92, 96.64% S: 1.27, 98.14%XVIII: 14.63, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.1 Hz, 3H), 1.73 (td, J = 10.5, 3.8 Hz, 2 H), 1.88 (s, 1 H), 2.27 (s, 3 H), 2.80(d, J = 10.5 Hz, 2 H), 2.97 (br. s., 1 H), 3.52 (s, 2 H), 4.26-4.08 (m,4 H), 5.48- 5.28 (m, 2 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.80 (d, J = 8.1Hz, 1 H), 7.89 (s, 1 H), 8.59 (s, 1 H), 9.07 (s, 1 H). 100-I

4-methyl-2-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-2H- 1,2,3-triazol-2-yl)pyrimidine-5- carbonitrile 445.2 S: 1.14, 94.5% R: 8.87, 97.32% XI:16.27, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.4 Hz, 3 H),1.87- 1.69 (m, 2 H), 2.30-2.21 (m, 3 H), 2.78-2.70 (m, 3 H), 2.82 (d, J= 11.0 Hz, 2H), 2.98 (br. s., 1 H), 3.78 (s, 2 H), 4.18 (d, J = 8.1 Hz,1 H), 5.45-5.27 (m, 2 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.80 (d, J = 8.1Hz, 1 H), 8.26 (s, 1 H), 9.31 (s, 1 H), (1 Exchangeable proton notobserved). 101-I

2-methoxy-4-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- imidazol-1-yl)benzonitrile 458.2 S: 1.28, 95.64% R: 0.88, 100% XI: 5.88, 100% ee ¹HNMR (400 MHz, DMSO-d6) δ 1.10-0.93 (m, 4 H), 1.83-1.68 (m, 2 H), 2.26(s, 3 H), 2.84 (t, J = 8.1 Hz, 2 H), 3.00-2.91 (m, 1 H), 3.46 (s, 2 H),4.08-3.95 (m, 3 H), 4.15 (d, J = 8.6 Hz, 1 H), 5.37 (s, 2 H), 7.41 (dd,J = 8.4, 1.8 Hz, 1 H), 7.48 (s, 1 H), 7.65 (d, J = 8.1 Hz, 1 H),7.92-7.75 (m, 3 H), 8.40 (s, 1 H). 102-I

4-methyl-5- ((2R,6S)-6-methyl- 4-((1-(2- methylpyridin-4-yl)-1H-pyrazol-4- yl)methyl)piperazin- 2- yl)isobenzofuran- 1(3H)-one418.2 S: 1.21, 100%. R: 0.63, 100%. XI: 4.31, 100% ee ¹H NMR (400 MHz,DMSO-d6) δ 1.34-1.23 (m, 3 H), 2.44-2.34 (m, 3 H), 2.59 (br. s., 1 H),2.69-2.63 (m, 3 H), 3.17 (d, J = 8.1 Hz, 2 H), 3.67 (br. s., 1 H), 3.80(br. s., 2 H), 4.77 (d, J =10.8 Hz, 2 H), 5.46 (q, J = 15.5 Hz, 2 H),7.90-7.76 (m, 2 H), 8.05-7.91 (m, 2 H), 8.09 (s, 1 H), 8.73 (d, J = 6.1Hz, 1 H), 8.81 (s, 1 H), (1 Exchangeable proton not observed). 103-I

4-methoxy-2-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- imidazol-1-yl)pyrimidine-5- carbonitrile 460.2 S: 1.28, 97.98%. R: 0.90, 97.82%.XVIII: 18.68, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.1 Hz, 3H), 1.88- 1.74 (m, 2 H), 1.92 (s, 1 H), 2.31- 2.24 (m, 3 H), 2.85 (t, J= 8.2 Hz, 2 H), 2.97 (br. s., 1 H), 3.56-3.48 (m, 2 H), 4.24-4.07 (m, 4H), 5.47- 5.30 (m, 2 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.87-7.74 (m, 2 H),8.62 (d, J = 1.2 Hz, 1 H), 9.09 (s, 1 H). 104-I

2-(4-(((3R,5R)-3- (hydroxymethyl)-5- (4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-2H-1,2,3-triazol-2-yl)- 4- methylpyrimidine- 5-carbonitrile 461.2 S: 0.95,96.95%. R: 0.82, 100%. ¹H NMR (400 MHz, DMSO-d6) 1.94-1.72 (m, 2 H),2.28 (s, 3 H), 2.79-2.70 (m, 4 H), 3.05-2.80 (m, 4 H), 3.45-3.35 (m, 1H), 3.80 (s, 2 H), 4.20 (d, J = 7.8 Hz, 1 H), 4.64 (t, J = 5.3 Hz, 1 H),5.48- 5.32 (m, 2 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 1H), 8.26 (s, 1 H), 9.30 (s, 1 H). 105-I

4-methyl-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- pyrazol-1-yl)nicotinonitrile 443.3 R: 1.01, 100% S: 1.48, 100% XXV: 6.28, 97.70%ee ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J = 6.1 Hz, 3 H), 1.72 (br.s., 2 H), 2.25 (s, 3 H), 2.58 (s, 3 H), 2.79 (d, J = 11.2 Hz, 2 H), 2.96(br. s., 1 H), 3.52 (s, 2 H), 4.16 (br. s., 1 H), 5.44-5.27 (m, 2 H),7.64 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.84 (s, 1 H),7.98 (s, 1 H), 8.51 (s, 1 H), 8.82 (s, 1 H), (1 Exchangeable proton notobserved). 106-I

4-methyl-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-1H- 1,2,3-triazol-1-yl)nicotinonitrile 444.3 R: 0.99, 100% S: 1.29, 98.10% XII: 19.17, 98.2%ee ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J = 5.9 Hz, 3 H), 1.80 (br.s., 2 H), 2.27 (s, 3 H), 2.64 (s, 3 H), 2.84 (br. s., 2H), 2.96 (br. s.,1 H), 3.75 (s, 2 H), 4.15 (br. s., 1 H), 5.45-5.30 (m, 2 H), 7.65 (d, J= 8.3 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 8.28 (s, 1 H), 8.77 (s, 1 H),8.98 (s, 1 H), (1 Exchangeable proton not observed). 107-I

4-methoxy-6-(4- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-2H- 1,2,3-triazol-2-yl)nicotinonitrile 460.3 R: 1.02, 95.00% S: 1.30, 94.00% XVIII: 16.50,100% ee ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J = 4.6 Hz, 3 H), 1.83(br. s., 2 H), 2.26 (s, 3 H), 2.81 (d, J = 6.6 Hz, 2 H), 2.97 (br. s., 1H), 3.77 (br. s., 2 H), 4.23- 4.07 (m, 4 H), 5.50-5.28 (m, 2 H),7.72-7.49 (m, 2 H), 7.79 (d, J = 7.6 Hz, 1 H), 8.22 (s, 1 H), 8.82 (s, 1H), (1 Exchangeable proton not observed). 108-I

3-methyl-1-(5- (((3S,5R)-3-methyl- 5-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1- yl)methyl)pyrimidin- 2-yl)-1H-pyrazole-4- 444.1 R: 1.01, 99.20% S: 1.33, 99.00% XII: 8.83, 100% ee ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J = 6.1 Hz, 3 H), 1.91-1.67 (m, 2H), 2.25 (s, 3 H), 2.42 (s, 3 H), 2.79 (t, J = 9.3 Hz, 2 H), 2.99 (br.s., 1 H), 3.63 (s, 2 H), 4.17 (d, J = 8.8 Hz, 1 H), 5.50- 5.24 (m, 2 H),7.66 (d, J = 8.1 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 8.83 (s, 2 H),9.35 (s, 1 H), (1 Exchangeable proton not observed). carbonitrile 109-I

5-(4-(((3R,5R)-3- (hydroxymethyl)-5- (4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin- 1-yl)methyl)-2H-1,2,3-triazol-2-yl)- 3- methylbenzo[d] oxazol-2(3H)-one 491.2 R: 1.26,100% S: 1.05, 95.00% XXVI: 3.72, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ ppm1.93-1.74 (m, 2 H), 2.28 (s, 3 H), 2.74 (s, 2 H), 3.03-2.80 (m, 2 H),3.37 (br.s., 2 H), 3.42 (s, 2 H), 3.80-3.68 (m, 2 H), 4.20 (d, J = 8.1Hz, 1 H), 4.65 (t, J = 5.5 Hz, 1 H), 5.46-5.33 (m, 2 H), 7.49 (d, J =8.8 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.75 (dd, J = 8.9, 2.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1 H), 7.84 (d, J = 2.4 Hz, 1 H), 8.05 (s, 1 H),(1 Exchangeable proton not observed). 110-I

6-(4-(((3R,4R)-4- hydroxy-3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H- pyrazol-1-yl)-4- methylnicotinonitrile444.2 C: 6.01, 99.30% G: 6.78, 99.30% X: 6.97 99% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.62 (d, J = 12.47 Hz, 1 H), 1.93 (d, J = 10.76 Hz, 1 H),2.04 (t, J = 11.25 Hz, 1 H), 2.14-2.20 (m, 1 H), 2.25 (s, 3 H), 2.58 (s,3 H), 2.74 (d, J = 11.74 Hz, 1 H), 2.93 (d, J = 10.03 Hz, 1 H), 3.01-3.12 (m, 1 H), 3.49-3.56 (m, 2 H), 3.71 (br. s., 1 H), 4.59 (br. s., 1H), 5.37 (d, J = 7.34 Hz, 2 H), 7.53 (d, J = 7.83 Hz, 1 H), 7.59- 7.65(m, 1 H), 7.85 (d, J = 1.71 Hz, 1 H), 7.98 (d, J = 0.73 Hz, 1 H), 8.52(s, 1 H), 8.83 (d, J = 1.96 Hz, 1 H). 111-I

6-(4-(((3R,4R)-4- hydroxy-3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-2H- 1,2,3-triazol-2-yl)- 4-methoxynicotinonitrile 461.1 R: 0.90, 95.30% S: 1.20, 94.00% XVIII:16.31, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.54 (m, 1 H), 1.93(d, J = 10.3 Hz, 1 H), 2.16 (t, J = 11.2 Hz, 1 H), 2.35-2.21 (m, 4 H),2.75 (d, J = 11.0 Hz, 1 H), 2.93 (d, J = 11.7 Hz, 1 H), 3.16-3.03 (m, 1H), 3.88-3.59 (m, 3 H), 4.12 (s, 3 H), 4.61 (d, J = 5.6 Hz, 1 H), 5.50-5.22 (m, 2 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H),7.68 (s, 1 H), 8.22 (s, 1 H), 8.82 (s, 1 H). 112-I

6-(4-(((3R,4R)-4- hydroxy-3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H- pyrazol-1-yl)-4- methoxynicotinonitrile460.2 R: 0.94, 100% S: 1.30, 100% XVIII: 12.2, 99.1% ee ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.63 (br. s., 1 H), 1.91 (s, 1 H), 2.05 (br. s., 1 H),2.25 (s, 4H), 2.75 (br. s., 1 H), 2.92 (br. s., 1 H), 3.07 (br. s., 1H), 3.53 (br. s., 2 H), 3.72 (br. s., 1 H), 4.10 (s, 3 H), 4.57 (br. s.,1 H), 5.45-5.26 (m, 2 H), 7.54 (br. s., 1 H), 7.72- 7.57 (m, 2 H), 7.87(br. s., 1 H), 8.52 (br. s., 1 H), 8.74 (s, 1 H).

Intermediate 53:4-methyl-6-(trimethylstannyl)nicotinonitrile

Intermediate 53 was prepared (1.80 g, crude) as a black syrup, by usinga similar synthetic protocol as that of Intermediate 23A and startingfrom 6-bromo-4-methylnicotinonitrile (1.00 g, 5.08 mmol). LCMS(Method-I): retention time 1.40 min, [M+H] 283.1. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 54-I:5-((3R,4R)-1-((2-bromothiazol-5-yl)methyl)-4-hydroxypiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 54-I was prepared (0.30 g, 21.77%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 23-I andstarting from Intermediate 52-I (0.36 g, 1.30 mmol) and Intermediate 25B(0.25 g, 1.30 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.58 (m, 1H),1.89-1.90 (m, 1H), 2.10 (br. S., 1H), 2.20-2.22 (m, 4H), 2.80 (br. S.,1H), 2.90 (br. S., 1H), 3.10 (br. S., 1H), 3.80-3.85 (m, 3H), 4.62 (br.S., 1H), 5.25-5.27 (m, 2H), 7.50-7.52 (m, 2H), 7.70 (d, J=8.00 Hz, 1H).LCMS (Method-1): retention time 1.01 min, [M+H] 423.2.

Intermediate 55-I:5-((2R,6S)-4-((2-bromothiazol-5-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 55-I was prepared (0.40 g, 60.60%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 23-I andstating from Intermediate 51-I (0.38 g, 1.56 mmol) and Intermediate 25B(0.30 g, 1.56 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (s, 3H), 1.80(br. s, 2H), 2.30 (s, 3H), 2.80 (br. s, 2H), 2.84 (br. s., 1H), 3.85 (s,2H), 4.16 (br. s., 1H), 5.37 (br. s., 2H), 7.79 (d, J=8.00 Hz, 1H),7.91-7.92 (m, 2H), (1 Exchangeable proton not observed). LCMS(Method-1): retention time 1.10 min, [M+H] 422.2.

Intermediate 56: 1-(2-methoxypyridin-4-yl)-1H-imidazole-4-carbaldehyde

Intermediate 56 was prepared (0.20 g, 19.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 11 andstarting from 1H-imidazole-4-carbaldehyde (0.51 g, 5.32 mmol) and4-bromo-2-methoxypyridine (1.00 g, 5.32 mmol). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 3.92 (s, 3H), 7.36 (d, J=1.60 Hz, 1H), 7.48-7.50 (m, 1H), 8.31 (d,J=6.00 Hz, 1H), 8.32 (d, J=1.20 Hz, 1H), 8.71 (d, J=6.00 Hz, 1H), 9.82(s, 1H). LCMS (Method-D): retention time 1.08 min, [M+H] 204.2.

Intermediate57:1-(2-(difluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 57 was prepared (0.12 g, 55.90%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 11 andstarting from 1H-pyrazole-4-carbaldehyde (0.11 g, 1.15 mmol) and(4-bromo-2-(difluoromethyl)pyridine (0.20 g, 0.96 mmol). LCMS(Method-S): retention time 0.49 min, [M+H] 224.3. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 58:1-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 58A: 4-bromo-1-(difluoromethyl)pyridin-2(1H)-one

To a solution of 4-bromo-2-chloropyridine (1.25 g, 6.72 mmol) in ACN(100 mL) was added NaHCO₃ (8.73 g, 10 mmol) and the resulting reactionmixture was heated at 80° C. for 30 minutes. A solution of2,2-difluoro-2-(fluorosulfonyl)acetic acid (5.38 mL, 52.00 mmol) in MeCN(15 mL) was added over 10 minutes and the reaction mixture was heated at80° C. for 2 h. The reaction mixture was cooled to ambient temperature,diluted with water (50 mL), basified with 10% aq. NaHCO₃ and extractedwith ethyl acetate (2×100 mL). The combined organic layers were washedwith brine (50 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to obtain Intermediate 58A (3.00 g, 25.80%) as apale yellow liquid. ¹H NMR (400 MHz DMSO-d₆) δ ppm 6.6 (dd, J=1.20, 3.20Hz, 1H), 7.56 (d, J=3.20 Hz, 1H), 7.75 (t, J=5.60 Hz, 1H), 7.8 (d,J=3.20 Hz, 1H). LCMS (Method-D): retention time 1.64 min [M+H] 224.2.

Intermediate 58

Intermediate 58 was prepared (0.10 g, 50.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from 1H-pyrazole-4-carbaldehyde (0.09 g, 0.89 mmol) andIntermediate 58A (0.20 g, 0.90 mmol). LCMS (Method-D): retention time0.73 min. [M+H] 240.2. The compound was taken directly to the subsequentstep without further purification or characterization.

Intermediate 59: (2-(5-cyano-4-methylpyridin-2-yl)oxazol-4-yl)methylmethanesulfonate

Intermediate 59A: ethyl2-(5-cyano-4-methylpyridin-2-yl)oxazole-4-carboxylate

To a solution of 6-bromo-4-methylnicotinonitrile (1.34 g, 7.09 mmol) intoluene (10 mL) was added ethyl oxazole-4-carboxylate (1.00 g, 7.09mmol), Cs₂CO₃ (4.62 g, 14.17 mmol) and tri-o-tolylphosphine (0.21 g,0.80 mmol). The resulting reaction mixture was degassed with nitrogenfor 20 minutes. Pd(OAc)₂ (0.16 g, 0.80 mmol) was added and the reactionmixture was degassed again for 10 minutes and then heated at 110° C. for12 h. The reaction mixture was cooled to ambient temperature, filteredthrough Celite® and the filtrate was evaporated under reduced pressure.The residue was purified by column chromatography (Redisep-40 g, 30%EtOAc/n-hexane) to obtain Intermediate 59A (0.25 g, 13.71%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (t, J=7.0 Hz, 3H), 2.60 (s,3H), 4.34 (q, J=7.00 Hz, 2H), 8.31 (s, 1H), 9.07 (s, 1H), 9.10 (s, 1H).LCMS (Method-D): retention time 1.99 min, [M+H] 258.2.

Intermediate 59B:6-(4-(hydroxymethyl)oxazol-2-yl)-4-methylnicotinonitrile

To a solution of Intermediate 59A (0.13 g, 0.51 mmol) in THE (10 mL) wasadded DIBAL-H (2.10 mL, 2.53 mmol) and the resulting reaction mixturewas stirred at ambient temperature for 1 h. The reaction mixture wasdiluted with a saturated solution of NH₄Cl (2 mL), water (10 mL) andextracted with 10% MeOH in DCM (2×20 mL). The combined organic layerswere washed with brine (10 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 59B (0.06 g,55.20%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.65 (s, 3H), 4.49 (br. s.,2H), 5.32 (br. s., 1H), 8.20 (s, 1H), 8.21 (s, 1H), 9.03 (s, 1H). LCMS(Method D): retention time 0.93 min [M+H] 216.2.

Intermediate 59

To a solution of Intermediate 59B (0.04 g, 0.19 mmol) in DCM (10 mL) wasadded TEA (0.08 mL, 0.56 mmol) and mesyl chloride (0.02 mL, 0.24 mmol)at 0° C. and the resulting reaction mixture was stirred at ambienttemperature for 30 minutes. The reaction mixture was diluted with water(5 mL) and extracted with DCM (2×20 mL). The combined organic layerswere washed with brine (10 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep-24 g, 60-70% EtOAc/n-hexane) to obtainIntermediate 59 (0.04 g, 73.40%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.60 (s, 3H), 3.23 (s, 3H), 5.75 (s, 2H), 8.25 (s, 1H),8.56 (s, 1H), 9.06 (s, 1H). LCMS (Method-D): retention time 1.65 min,[M+H] 294.0.

Intermediate 60: 6-(5-formyloxazol-2-yl)-4-methylnicotinonitrile

Intermediate 60A: Ethyl2-(5-cyano-4-methylpyridin-2-yl)oxazole-5-carboxylate

Intermediate 60A was prepared (0.50 g, 34.30%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 59A andstarting from ethyl oxazole-5-carboxylate (0.80 g, 5.67 mmol) and6-bromo-4-methylnicotinonitrile (1.11 g, 5.67 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.34 (t, J=7.00 Hz, 3H), 2.60 (s, 3H), 4.34 (q, J=7.00Hz, 2H), 8.26 (s, 1H), 8.30 (s, 1H), 9.10 (s, 1H). LCMS (Method-D):retention time 2.26 min, [M+H] 258.2.

Intermediate 60B:6-(5-(hydroxymethyl)oxazol-2-yl)-4-methylnicotinonitrile

To a solution of Intermediate 60A (0.10 g, 0.34 mmol) in a mixture ofTHE (10 mL) and MeOH (2 mL) was added NaBH₄ (0.05 g, 1.17 mmol) at 0° C.and the resulting reaction mixture was stirred at ambient temperaturefor 30 minutes. The reaction mixture was diluted with water (20 mL) andextracted with 10% MeOH in DCM (2×30 mL). The combined organic layerswere washed with brine (20 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep-4 g, 60-70% EtOAc/n-Hexane) to obtainIntermediate 60B (0.04 g, 47.80%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.60 (s, 3H), 5.65 (t, J=5.60 Hz, 1H), 5.85-5.99 (m, 1H),7.36 (s, 1H), 8.18 (s, 1H), 9.03 (s, 1H), (1 Exchangeable proton notobserved). LCMS (Method-I): retention time 0.70 min, [M+H]216.2.

Intermediate 60

Intermediate 60 was prepared (0.06 g, 87.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 60B (0.07 g, 0.32 mmol) and Dess-Martinperiodinane (0.18 g, 0.43 mmol). LCMS (Method-1): retention time 0.60min, [M+H] 214.2. The compound was taken directly to the subsequent stepwithout further purification or characterization.

Intermediate 61:1-(6-(difluoromethyl)pyridin-3-yl)-1H-imidazole-4-carbaldehyde

Intermediate 61 was prepared (0.03 g, 13.98%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from 4-bromo-2-(difluoromethyl)pyridine (0.20 g, 0.96 mmol) and1H-imidazole-4-carbaldehyde (0.09 g, 0.96 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.00 (t, J=7.20 Hz, 1H), 7.94-7.91 (m, 1H), 8.44-8.41 (m,1H), 8.64 (s, 1H), 9.85 (s, 1H)), 8.80 (d, J=1.60 Hz, 1H), 9.16 (d,J=3.20 Hz, 1H). LCMS (Method-1): retention time 0.66 min [M+H] 224.0.

Intermediate 62: 4-methyl-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 62 was prepared (0.21 g, 54.10%), by using a similarsynthetic protocol as that of Intermediate 15C and starting from4-methyl-1H-imidazole (0.24 g, 2.89 mmol) and6-chloro-4-methylnicotinaldehyde (0.30 g, 1.93 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.19 (d, J=0.98 Hz, 3H), 2.69 (s, 3H), 7.75 (d, J=1.22Hz, 1H), 7.80 (s, 1H), 8.53 (d, J=1.22 Hz, 1H), 8.85 (s, 1H), 10.21 (s,1H). LCMS (Method-D): retention time 1.20 min, [M+H] 202.2.

Intermediate 63:2-methyl-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 63 was prepared (0.25 g, 64.40%), by using a similarsynthetic protocol as that of Intermediate 15C and starting from4-methyl-1H-imidazole (0.24 g, 2.89 mmol) and6-chloro-2-methylnicotinaldehyde (0.30 g, 1.93 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.19 (d, J=0.98 Hz, 3H), 2.69 (s, 3H), 7.75 (d, J=1.22Hz, 1H), 7.80 (s, 1H), 8.53 (d, J=1.22 Hz, 1H), 8.85 (s, 1H), 10.21 (s,1H). LCMS (Method-D): retention time 1.20 min, [M+H] 202.2.

Intermediate64:5′-formyl-4,6′-dimethoxy-[2,2′-bipyridine]-5-carbonitrile

Intermediate 64A: 6-chloro-2-methoxynicotinaldehyde

Synthesized according to literature procedures (EP1405859 A1, 2004).

Intermediate 64

Intermediate 64 was prepared (0.15 g, 39.10%) as a pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 23B andstarting from Intermediate 23A (0.62 g, 2.09 mmol) and Intermediate 64A(0.30 g, 1.75 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.14-4.24 (m, 6H),8.15-8.22 (m, 2H), 8.28-8.36 (m, 1H), 8.95-9.01 (m, 1H), 10.27-10.35 (m,1H). LCMS (Method-D): retention time 2.603 min, [M+H]270.1.

Intermediate 65: 5-fluoro-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 65 was prepared (0.18 g, 59.70%) as a pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 11 andstarting from 4-methyl-1H-imidazole (0.18 g, 2.20 mmol) and6-bromo-5-fluoronicotinaldehyde (0.30 g, 1.47 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.18-2.24 (m, 3H), 7.63-7.72 (m, 1H), 8.31-8.44 (m, 2H),8.87-8.92 (m, 1H), 10.04-10.13 (m, 1H). LCMS (Method-D): retention time1.16 min, [M+H] 206.0.

Intermediate 66:6-(4-formyl-5-methyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 66 was prepared (0.09 g, 14.60%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from 3-methyl-1H-pyrazole-4-carbaldehyde (0.40 g, 3.63 mmol)and 6-bromo-4-methylnicotinonitrile (0.54 g, 2.72 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.15 (s, 3H), 2.32 (s, 3H), 7.89-7.94 (m, 1H),7.97-8.07 (m, 1H), 8.38-8.46 (m, 1H), 8.75-8.83 (m, 1H). LCMS(Method-O): retention time 1.14 min, [M+H] 227.0.

Intermediate 67:6-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)nicotinaldehyde

Intermediate 67A: (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methanol

To a stirred solution of 6-chloro-4-(trifluoromethyl)nicotinate (2.00 g,8.35 mmol) in toluene (25 mL) at −78° C. was added 1M DIBAL-H in toulene(12.52 mL, 12.52 mmol) and the reaction mixture was stirred at −78° C.for 2 h. The resulting reaction mixture was diluted with saturated NH₄Cl(40 mL) and extracted with ethyl acetate (2×75 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain Intermediate 67A(2.20 g, 87.00%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.70 (s, 2H),5.65-5.77 (m, 1H), 7.88 (s, 1H), 8.76 (s, 1H). LCMS: The compound didnot ionize well.

Intermediate 67B: 6-chloro-4-(trifluoromethyl)nicotinaldehyde

Intermediate 67B was prepared (0.97 g, 75.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 67A (1.30 g, 6.14 mmol) and Dess-Martin periodinane (2.61g, 6.14 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.16 (s, 1H), 9.11 (s,1H), 10.24 (q, J=1.71 Hz, 1H). LCMS: The compound did not ionize well.

Intermediate 67

Intermediate 67 was prepared (0.23 g, 47.20%), by using a similarsynthetic protocol as that of Intermediate 15C and starting fromIntermediate 67B (0.30 g, 1.43 mmol) and 4-methyl-1H-imidazole (0.17 g,2.15 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.72-3.76 (m, 3H), 6.88-6.95(m, 2H), 7.10-7.17 (m, 2H), 7.77-7.81 (m, 1H). LCMS (Method-O):retention time 1.05 min, [M+H] 256.4.

Intermediate 68:2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidine-5-carbaldehyde

Intermediate 68A: 4,5-dimethyl-1H-imidazole

Synthesized according to literature procedures (Angewandte Chemie,5322-5326, 49, 2010).

Intermediate 68

To a solution of 2-bromopyrimidine-5-carbaldehyde (0.20 g, 1.07 mmol) inACN (20 mL) was added K₂CO₃ (443 mg, 3.21 mmol) followed by Intermediate68A (0.16 g, 1.60 mmol) and the resulting reaction mixture was stirredat 50° C. for 1.5 h. The reaction mixture cooled to ambient temperature,diluted with ethyl acetate (30 mL) and filtered through Celite®. Thefiltrate was evaporated under reduced pressure to obtain Intermediate 68(0.19 g, 86.00%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.13(d, J=0.49 Hz, 3H), 2.16 (s, 3H), 8.47 (s, 1H), 9.27 (s, 2H), 10.11 (s,1H). LCMS: The compound did not ionize well.

Intermediate 69: 4-methoxy-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 69A: methyl 6-chloro-4-methoxynicotinate

Synthesized according to literature procedures (US2015/166505 A1, 2015).

Intermediate 69B: (6-chloro-4-methoxypyridin-3-yl)methanol

To a stirring solution of Intermediate 69A (2.20 g, 10.91 mmol) in DCM(30 mL) was added 1M DIBAL-H in heptane (16.37 mL, 16.37 mmol) at 0° C.and the resulting reaction mixture was stirred at ambient temperaturefor 1 h. The resulting reaction mixture was diluted with saturated NH₄Cl(40 mL) and extracted with DCM (3×50 mL). The combined organic layerswere washed with brine (30 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep-24 g, 20% EtOAc/n-hexane) to obtain Intermediate69B (1.20 g, 63.30%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.88 (s, 3H) 4.46(dd, J=5.52, 1.00 Hz, 2H), 5.19 (t, J=5.77 Hz, 1H), 7.11 (s, 1H), 8.16(s, 1H). LCMS (Method-1): retention time 0.69 min, [M+H] 174.4.

Intermediate 69C: 6-chloro-4-methoxynicotinaldehyde

Intermediate 69C was prepared (0.75 g, 63.20%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 69B (1.20 g, 6.91 mmol) and Dess-Martin periodonane (2.93g, 6.91 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.02 (s, 3H), 7.45 (s,1H), 8.55 (s, 1H), 10.24 (s, 1H). LCMS (Method-D): retention time 1.06min, [M+H] 172.2.

Intermediate 69

Intermediate 69 was prepared (0.12 g, 37.80%), by using a similarsynthetic protocol as that of Intermediate 68 and starting fromIntermediate 69C (0.25 g, 1.46 mmol) and 4-methyl-1H-imidazole (0.24 g,2.91 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.19 (s, 3H), 4.09 (s, 3H),7.49 (s, 1H), 7.81 (s, 1H), 8.56 (d, J=1.00 Hz, 1H), 8.63 (s, 1H), 10.23(s, 1H). LCMS (Method-1): retention time 0.89 min, [M+H] 218.3.

Intermediate 70:2-(5-(difluoromethyl)-4-methyl-1H-imidazol-1-yl)pyrimidine-5-carbaldehyde

Intermediate 70A: tert-butyl5-formyl-4-methyl-1H-imidazole-1-carboxylate

Intermediate 70A was prepared (2.80 g, 73.30%) as a white solid, byusing a similar synthetic protocol as that of Intermediate 18B-II andstarting from 4-methyl-1H-imidazole-5-carbaldehyde (2.00 g, 18.16 mmol)and BOC₂O (5.06 mL, 21.80 mmol). LCMS (Method-1): retention time 1.07min, [M−56] 155.9. The compound was taken directly to the subsequentstep without further purification or characterization.

Intermediate 70B: tert-butyl5-(difluoromethyl)-4-methyl-1H-imidazole-1-carboxylate

Intermediate 70B was prepared (0.85 g, 51.30%), by using a similarsynthetic protocol as that of Intermediate 4B and starting fromIntermediate 70A (1.50 g, 7.14 mmol) and DAST (1.89 mL, 14.27 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.58 (s, 9H), 2.44 (t, J=2.26 Hz, 3H),6.82-7.18 (m, 1H), 8.19 (s, 1H). The compound did not ionize well.

Intermediate 70C: 5-(difluoromethyl)-4-methyl-1H-imidazole

Intermediate 70C was prepared (0.48 g, 99.00%), by using a similarsynthetic protocol as that of Intermediate 4C and starting fromIntermediate 70B (0.85 g, 3.66 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.38 (t, J=2.08 Hz, 3H), 7.06-7.52 (m, 1H), 9.02 (s, 1H), (1Exchangeable proton not observed). LCMS (Method-1): retention time 0.58min, [M+H] 133.4.

Intermediate 70

Intermediate 70 was prepared (0.10 g, 20.90%), by using a similarsynthetic protocol as that of Intermediate 68 and starting fromIntermediate 70C (0.28 g, 1.68 mmol) and2-chloropyrimidine-5-carbaldehyde (0.20 g, 1.40 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.69 (t, J=2.32 Hz, 3H), 6.92-7.26 (m, 1H), 8.62 (s, 1H),9.34 (s, 2H), 10.15 (s, 1H). LCMS (Method-D): retention time 1.50 min,[M+H] 239.0.

Intermediate 71-I and 71-II:4-methyl-5-(3-methylpiperazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 71A:4-methyl-5-(3-methylpyrazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 71A was prepared (3.00 g, 65.50%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 2B (5.00 g, 18.24 mmol) and2-Chloro-3-methylpyrazine (2.81 g, 21.89 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.03 (s, 3H), 2.32 (s, 3H), 5.49 (s, 2H), 7.51 (d, J=8.03Hz, 1H), 7.79 (d, J=7.53 Hz, 1H), 8.56-8.64 (m, 2H). LCMS (Method-O):retention time 0.77 min, [M+H] 241.4.

Intermediate 71-I and 71-II

Intermediate 71-I and 71-II was prepared by using a similar syntheticprotocol as that of Intermediate 2-I and 2-II and starting fromIntermediate 71A (10.00 g, 41.6 mmol). The racemate was separated intotwo individual enantiomers by SFC [Chiralpak AD-H (250×4.6 mm), 5micron; 0.2% NH₄OH in MeOH+ACN (1:1), Flow: 1.2 mL/min. Temperature: 27°C., UV: 235 nm]. First eluted compound (retention time 3.37 min),designated as Intermediate 71-I, was obtained (0.65 g, 21.13%) as abrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.7 (d, J=6.02 Hz, 3H),2.14-2.22 (m, 2H), 2.29 (s, 3H), 2.74-2.84 (m, 3H), 4.02 (dd, J=10.04,2.51 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.81 (d, J=8.03 Hz,1H), (2 Exchangeable protons not observed). LCMS (Method-0): retentiontime 0.77 min, [M+H] 241.4. Second eluted compound (retention time 4.79min), designated as Intermediate 71-II, was obtained (1.20 g, 39.00%) asa brown solid. LCMS (Method-O): retention time 0.77 min, [M+H] 241.4. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.70 (d, J=6.02 Hz, 3H), 2.14-2.22 (m, 2H),2.29 (s, 3H), 2.74-2.84 (m, 3H), 4.02 (dd, J=10.04, 2.51 Hz, 1H), 5.38(s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.81 (d, J=8.03 Hz, 1H), (2Exchangeable protons not observed).

Intermediate 72:5-(4-hydroxy-4-methylpiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 72A: tert-butyl4-hydroxy-4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirring solution of Intermediate 4A (1.80 g, 5.21 mmol) in THE (20mL) was added 3M methylmagnesium chloride in THE (5.21 mL, 15.63 mmol)at 0° C. and the resulting reaction mixture was stirred at ambienttemperature for 1 h. Reaction mixture was diluted with saturated NH₄Cl(40 mL) and extracted with EtOAc (3×50 mL). The combined organic layerswere washed with brine (30 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep-40 g, 20-40% EtOAc/n-hexane) to obtainIntermediate 72A (1.00 g, 53.10%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94(s, 3H), 1.39 (s, 9H), 1.59 (br. s., 2H), 1.89 (s, 1H), 2.27 (s, 3H),2.88-2.96 (m, 1H), 3.52-3.65 (m, 1H), 3.79-3.94 (m, 1H), 4.61-4.72 (m,1H), 5.40 (s, 2H), 7.61 (d, J=8.03 Hz, 1H), 7.82-7.93 (m, 1H), (1Exchangeable proton not observed). LCMS (Method-D): retention time 2.22min, [M+H] 362.2.

Intermediate 72

Intermediate 72 was prepared (0.90 g, 87.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 19-I andstarting from Intermediate 72A (1.00 g, 2.77 mmol) and TFA (4 mL, 51.9mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (s, 3H), 1.71-1.84 (m, 1H),1.87-1.96 (m, 1H), 2.28 (s, 3H), 2.96-3.02 (m, 1H), 3.26 (br. s., 2H),3.37 (br. s., 2H), 5.41 (d, J=5.02 Hz, 2H), 7.66 (d, J=8.03 Hz, 1H),7.76 (d, J=8.53 Hz, 1H), (2 Exchangeable protons not observed). LCMS(Method-O) retention time 0.52 min, [M+H] 262.2.

Intermediate 73-I:5-(4-hydroxy-5,5-dimethylpiperidin-3-yl)-4-methylisobenzofuran-1(3H)-onehydrochloride (Diastereomer-I:Enantiomer-I

Intermediate 73A: tert-butyl3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-oxopiperidine-1-carboxylate

Intermediate 73A was prepared (2.30 g, 28.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 4A andstarting from Intermediate 2A (5.00 g, 22.02 mmol) and tert-butyl3,3-dimethyl-4-oxopiperidine-1-carboxylate (10.01 g, 44.0 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.01-1.07 (m, 3H), 1.21-1.26 (m, 3H), 1.46 (s,9H), 2.28 (s, 3H), 2.11-2.18 (m, 4H), 4.34-4.44 (m, 1H), 5.35-5.44 (m,2H), 7.35-7.42 (m, 1H), 7.60-7.70 (m, 1H). LCMS (Method-O): retentiontime 1.29 min, [M+H] 374.6.

Intermediate 73B-I and 73B-II: tert-butyl4-hydroxy-3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirring solution of Intermediate 73A (3.50 g, 9.37 mmol) in MeOH(20 mL) was added 2M LiBH₄ in THE (4.69 mL, 9.37 mmol) and the resultingreaction mixture was stirred at ambient temperature for 2 h. Thereaction mixture was concentrated to dryness under reduced pressure,diluted with water (50 mL), and extracted with 10% MeOH in DCM (3×50mL). The combined organic layers were washed with brine (30 mL), driedover anhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by preparative HPLC [Sunfire C18 (250×4.6 mm) 5micron; 10 mM Ammonium acetate in water, Solvent B: Acetonitrile,Gradient: 30-100% B over 16 min, Flow: 25 mL/min UV: 250 nm] to obtaindiastereomer-I and II. The diastereomer-I was separated into twoindividual enantiomers by supercritical fluid chromatography (SFC)[Chiralpak AD-H (250×4.6 mm), 5 micron; 0.2% NH₄OH in MeOH, Flow: 1.2mL/min. Temperature: 30° C., UV: 240 nm]. First eluted compound(retention time 4.17 min), designated as Intermediate 73B-I, wasobtained (0.75 g, 21.31%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.82-0.98 (m, 6H), 1.41 (s, 9H), 2.28 (s, 3H), 2.61-2.85(m, 2H), 3.01-3.14 (m, 1H), 3.54-3.69 (m, 1H), 3.79-3.99 (m, 1H),4.53-4.67 (m, 1H), 5.40 (s, 2H), 7.59 (s, 1H), 7.66 (s, 1H), (1Exchangeable proton not observed). LCMS (Method-D): retention time 2.69min, [M−55] 320.2. Chiral purity (Method-XXII): retention time 4.3 min,100% ee. Second eluted compound (retention time 7.81 min), designated asIntermediate 73B-II, was obtained (0.80 g, 22.73%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82-0.98 (m, 6H), 1.41 (s, 9H),2.28 (s, 3H), 2.61-2.85 (m, 2H), 3.01-3.14 (m, 1H), 3.54-3.69 (m, 1H),3.79-3.99 (m, 1H), 4.53-4.67 (m, 1H), 5.40 (s, 2H), 7.59 (s, 1H), 7.66(s, 1H), (1 Exchangeable proton not observed). LCMS (Method-D):retention time 2.47 min, [M−55] 320.2. Chiral purity (Method-XXXII):retention time 8.43 min, 99.50% ee.

Intermediate 73-I

Intermediate 73-I was prepared (0.60 g, 96.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 52-I andstarting from Intermediate 73B-I (0.75 g, 1.20 mmol) and 4N HCl indioxane (6 mL, 24.00 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (s,3H), 1.12 (s, 3H), 2.31 (s, 4H), 2.92-3.02 (m, 1H), 3.07-3.17 (m, 3H),3.42-3.49 (m, 1H), 3.70-3.80 (m, 1H), 4.81-4.91 (m, 1H), 5.36-5.45 (m,2H), 7.61-7.67 (m, 1H), 7.72-7.77 (m, 1H). LCMS (Method-D): retentiontime 0.53 min, [M+H] 276.2.

Intermediate 74:2-(4-formyl-2H-1,2,3-triazol-2-yl)-4,6-dimethylpyrimidine-5-carbonitrile

Intermediate 74A:2-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4,6-dimethylpyrimidine-5-carbonitrile

Intermediate 74A was prepared (0.80 g, 9.84%), by using a similarsynthetic protocol as that of Intermediate 42 and starting fromIntermediate 28A (3.50 g, 35.30 mmol) and Intermediate 42C (7.49 g,35.30 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.68-2.76 (m, 6H), 4.69 (s,2H), 8.21 (s, 1H), (1 Exchangeable proton not observed).

Intermediate 74

Intermediate 74 was prepared (0.81 g, 86.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 74A (0.95 g, 4.13 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.79 (s, 6H), 8.79 (s, 1H), 10.24 (s, 1H). LCMS (Method-D): retentiontime 0.706 min, [M+H] 229.0.

Intermediate 75:5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)oxazol-2(3H)-one

Intermediate 75A: ethyl 2-oxo-3-trityl-2,3-dihydrooxazole-5-carboxylate

To a stirred solution of ethyl 2-oxo-2,3-dihydrooxazole-5-carboxylate(1.50 g, 9.55 mmol, commercial) in DCM (20 mL) was added TEA (3.99 mL,28.6 mmol) followed by trityl chloride (2.66 g, 9.55 mmol) and theresulting mixture was stirred at ambient temperature for 14 h. Thereaction mixture was diluted with water (30 mL) and extracted with DCM(3×50 mL). The combined organic layers were washed with brine (30 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-40g, 10-20% EtOAc/n-hexane) to obtain Intermediate 75A (3.20 g, 84.00%) asa white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.22 (t, J=7.10 Hz, 3H),4.22 (q, J=7.10 Hz, 2H), 7.22-7.42 (m, 15H), 7.50 (s, 1H). LCMS: Thecompound did not ionize well.

Intermediate 75B: 5-(hydroxymethyl)-3-trityloxazol-2(3H)-one

Intermediate 75B was prepared (1.70 g, 59.40%) as a white solid, byusing a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 75A (3.20 g, 8.01 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 4.15 (d, J=4.79 Hz, 2H), 5.24 (t, J=5.04 Hz, 1H), 6.63(s, 1H), 7.18-7.44 (m, 15H). LCMS: The compound did not ionize well.

Intermediate 75C: 2-oxo-3-trityl-2,3-dihydrooxazole-5-carbaldehyde

Intermediate 75C was prepared (1.00 g, 59.20%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 75B (1.7 g, 4.76 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.18-7.44 (m, 15H), 8.167 (s, 1H), 9.25 (s, 1H). LCMS: The compound didnot ionize well.

Intermediate 75_(D):5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-3-trityloxazol-2(3H)-one

Intermediate 75_(D) was prepared (0.52 g, 63.10%), by using a similarsynthetic protocol as that of Intermediate 4 and starting fromIntermediate 75C (0.50 g, 1.41 mmol) and Intermediate 51-I (0.45 g, 1.83mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.95-1.04 (m, 3H), 1.64-1.79 (m,2H), 2.24 (s, 4H), 2.61-2.74 (m, 3H), 2.83-2.95 (m, 2H), 5.41 (s, 2H),6.63-6.71 (m, 1H), 7.13-7.38 (m, 15H), 7.64-7.71 (m, 1H), 7.74-7.82 (m,1H), (1 Exchangeable proton not observed). LCMS (Method-D): retentiontime 3.12, [M+H] 586.6.

Intermediate 75

To a solution of Intermediate 75_(D) (0.52 g, 0.89 mmol) in DCM (10 mL)was added TFA (3 mL, 38.9 mmol) at 0° C. and the resulting reactionmixture was stirred at ambient temperature for 2 h. The reaction mixturewas concentrated to dryness, diluted with diethyl ether (100 mL), Thesolid precipitate was filtered and dried under vacuum to obtain (0.32 g,64.25%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (d, J=6.53 Hz, 3H), 2.37(s, 5 H), 3.02-3.14 (m, 2H), 3.53 (d, J=4.52 Hz, 2H), 3.61-3.74 (m, 1H),4.74-4.83 (m, 1H), 5.47 (d, J=10.54 Hz, 2H), 6.88 (d, J=2.01 Hz, 1H),7.82 (s, 1H), 7.87 (s, 1H), 10.49-10.56 (m, 1H), (1 Exchangeable protonnot observed). LCMS (Method-O): retention time 0.57 min, [M+H] 344.4.

Intermediate 76:1-(3-methyl-5-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrazole-4-carbaldehyde

Intermediate 76A: 2-chloroethyl (3-bromo-5-methylphenyl)carbamate

To a stirring solution of 3-bromo-5-methylaniline (5.00 g, 26.9 mmol) inTHE (100 mL) was added K₂CO₃ (11.14 g, 81 mmol) followed by2-chloroethyl chloroformate (4.16 mL, 40.3 mmol) and the resultingreaction mixture was refluxed for 4 h. The reaction mixture was cooledto ambient temperature, diluted with 5% NaHCO₃ solution (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 76A (7.00 g,89.00%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H),3.81-3.95 (m, 2H), 4.32-4.42 (m, 2H), 7.04 (s, 1H), 7.26 (s, 1H), 7.55(s, 1H), 9.96 (s, 1H). LCMS (Method-D): retention time 2.99 min, [M+H]291.0.

Intermediate 76B: 3-(3-bromo-5-methylphenyl)oxazolidin-2-one

To a solution of Intermediate 76A (7.00 g, 23.93 mmol) in THE (80 mL)was added NaH (2.39 g, 59.80 mmol) and the resulting reaction mixturewas stirred at ambient temperature for 4 h. The reaction mixture wasdiluted with water (30 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-40 g, 50%EtOAc/n-hexane) to obtain Intermediate 76B (4.20 g, 68.50%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H), 3.98-4.08 (m, 2H),4.41-4.49 (m, 2H), 7.16 (s, 1H), 7.29-7.36 (m, 1H), 7.69 (t, J=1.76 Hz,1H). LCMS (Method-D): retention time 2.37 min, [M+H]257.4.

Intermediate 76

Intermediate 76 was prepared (0.06 g, 7.00%), by using a similarsynthetic protocol as that of Intermediate 6 and starting fromIntermediate 76B (0.96 g, 3.75 mmol) and 1H-pyrazole-4-carbaldehyde(0.30 g, 3.12 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.25-2.43 (m, 3H),3.99-4.19 (m, 2H), 4.31-4.53 (m, 2H), 6.47-6.62 (m, 1H), 7.06-7.14 (m,1H), 7.19-7.24 (m, 1H), 7.41-7.58 (m, 1H), 8.28 (s, 1H), 9.24 (s, 1H).LCMS (Method-O): retention time 1.05 min, [M+H] 272.3.

Intermediate 77: 6-(1H-1,2,4-triazol-1-yl)nicotinaldehyde

Intermediate 77 was prepared (0.3 g, 49.30%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from6-bromonicotinaldehyde (0.50 g, 2.69 mmol) and 4H-1,2,4-triazole (0.204g, 2.96 mmol). ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J 8.31 Hz, 1H),8.41 (br. s., 1H), 8.51 (d, J 7.83 Hz, 1H), 9.07 (br. s., 1H), 9.52 (br.s., 1H), 10.15 (br. s., 1H). LCMS (Method-O): retention time 0.62 min,[M+H] 175.2.

Intermediate 78: 6-(4-formyl-1H-pyrazol-1-yl)-4-isopropoxynicotinonitrile

Intermediate 78 was prepared (0.45 g, 54.00%) as a pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 6-chloro-4-isopropoxynicotinonitrile (0.61 g, 3.12 mmol)and 1H-pyrazole-4-carbaldehyde (0.30 g, 3.12 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.36 (d, J=6.05 Hz, 6H), 5.09-5.16 (m, 1H), 7.69 (s, 1H),8.39 (s, 1H), 8.84 (s, 1H), 9.37 (d, J=0.55 Hz, 1H), 9.99 (s, 1H). LCMS(Method-J): retention time 2.36 min, [M+H] 257.2.

Intermediate 79:1-(5-formylpyridin-2-yl)-1H-pyrazole-4-carboxamide

Intermediate 79A: 2-chloro-5-(1,3-dioxolan-2-yl)pyridine (Intermediate-I

To a stirred solution of 6-chloronicotinaldehyde (5.00 g, 35.30 mmol) intoluene (100 mL) was added ethane-1,2-diol (2.63 g, 42.4 mmol), p-TsOH(0.67 g, 3.53 mmol) and the reaction mixture was refluxed underDean-Stark conditions for 6 h. The reaction mixture was cooled toambient temperature and washed with saturated NaHCO₃ (50 mL) and brine(50 mL). The separated organic layer was dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain Intermediate 79A(5.50 g, 77.00%) as a yellow liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.95-4.00 (m, 4H), 5.85 (s, 1H), 7.56 (m, J=8.25, 0.43 Hz, 1H), 7.91(dd, J=8.25, 2.45 Hz, 1H), 8.48 (dd, J=1.83, 0.49 Hz, 1H). LCMS(Method-O): retention time 0.85 min, [M+H] 188.3.

Intermediate 79B: ethyl1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylate

Intermediate 79B was prepared (0.80 g, 27.40%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from Intermediate 79A (1.50 g, 8.08 mmol) and1H-pyrazole-4-carboxylate (1.25 g, 8.89 mmol). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.31 (t, J=7.09 Hz, 3H), 3.98-4.02 (m, 2H), 4.08-4.13 (m, 2H),4.28 (q, J=7.09 Hz, 2H), 5.90 (s, 1H), 8.01 (dd, J=8.44, 0.60 Hz, 1H),8.08-8.11 (m, 1H), 8.23 (d, J=0.69 Hz, 1H), 8.58 (d, J=2.13 Hz, 1H),9.00 (d, J=0.69 Hz, 1H). LCMS (Method-J): retention time 2.39 min, [M+H]290.1.

Intermediate 79C:1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

To a stirred solution of Intermediate 79B (0.35 g, 1.21 mmol) in EtOH(10 mL) was added ammonium hydroxide (10 mL, 257 mmol) and the reactionmixture was heated at 60° C. for 40 h. The reaction mixture was cooledto ambient temperature, concentrated to dryness, diluted with water (20mL) and extracted with 10% MeOH in DCM (3×30 mL). The combined organiclayers were washed with brine (20 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain Intermediate 79C(0.20 g, 55.30%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.98-4.03 (m, 2H), 4.09-4.13 (m, 2H), 5.90 (s, 1H), 7.24 (br. s, 1H),7.84 (br. s, 1H), 7.98-8.01 (m, 1H), 8.09 (d, J=2.14 Hz, 1H), 8.15 (d,J=0.55 Hz, 1H), 8.57 (d, J=2.02 Hz, 1H), 9.15 (d, J=0.61 Hz, 1H). LCMS(Method-J): retention time 0.60 min, [M+H] 261.1.

Intermediate 79

To a stirred solution of Intermediate 79C (0.20 g, 0.77 mmol) in amixture of toluene (3 mL) and water (0.5 mL) was added p-TsOH (0.22 g,1.15 mmol) and the reaction mixture was heated at 70° C. for 1 h. Thereaction mixture was concentrated to dryness, diluted with water (30 mL)and the solid precipitate obtained was isolated by suction filtrationand dried under vacuum to obtain Intermediate 79 (0.120 g, 62.80%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.30 (br. s., 1H), 7.88(br. s., 1H), 8.13 (d, J=8.53 Hz, 1H), 8.22 (d, J=0.69 Hz, 1H), 8.46(dd, J=8.53, 2.20 Hz, 1H), 9.05 (dd, J=2.13, 0.69 Hz, 1H), 9.24 (d,J=0.69 Hz, 1H), 10.12 (s, 1H). LCMS (Method-J): retention time 0.60 min,[M+H] 216.1.

Intermediate 80: 1-(5-formylpyridin-2-yl)-1H-pyrazole-3-carbonitrile

Intermediate 80 was prepared (0.45 g, 84.00%) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 1H-pyrazole-3-carbonitrile (0.02 g, 2.96 mmol) and6-bromonicotinaldehyde (0.05 g, 2.69 mmol). ¹H NMR (400 MHz, DMSO-d₆) δppm 7.53 (d, J=2.40 Hz, 1H), 8.19 (d, J=8.00 Hz, 1H), 8.49-8.52 (M, 1H),8.99 (d, J=2.40 Hz, 1H), 9.07 (d, J=1.20 Hz, 1H), 10.15 (s, 1H). LCMS(Method-D): retention time 1.95 min, [M+H] 199.0.

Intermediate 81: 4-ethoxy-6-(4-formyl-1H-pyrazol-1-yl)nicotinonitrile

Intermediate 81A: 6-chloro-4-ethoxynicotinonitrile

Synthesized according to literature procedures (PCT 2016091042, 2016).

Intermediate 81

Intermediate 81 was prepared (0.30 g, 41.70%), by using a similarsynthetic protocol as that of Intermediate 20 and starting fromIntermediate 81A (0.30 g, 1.66 mmol) and 1H-pyrazole-4-carboxylate (0.20g, 1.66 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (d, J=7.20 Hz, 3H),4.40 (q, J=7.20 Hz, 2H), 8.38 (s, 1H), 8.69 (s, 1H), 8.84 (s, 1H), 9.36(s, 1H), 9.98 (s, 1H). LCMS (Method-D): retention time 2.12 min, [M+H]243.2.

Intermediate 82:1-(3,4-dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 82A: 5-bromo-3,4-dimethylbenzo[d]oxazol-2(3H)-one

Synthesized according to literature procedures (PCT2017/001991, 2017).

Intermediate 82

To a stirred solution of 1H-pyrazole-4-carbaldehyde (0.25 g, 2.60 mmol)and Intermediate 82A (0.69 g, 2.86 mmol) in DMSO (5 mL) was added K₂CO₃(0.90 g, 6.50 mmol) and was degassed with nitrogen for 5 minutes. To theresulting reaction mixture was added copper (I) iodide (0.25 g, 1.30mmol) followed by N,N-dimethylglycine (0.13 g, 1.30 mmol) and was heatedat 110° C. for 16 h. The reaction mixture was cooled to ambienttemperature, diluted with water (40 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (Redisep-24 g, 20-40% EtOAc/n-hexane)to obtain (0.35 g, 40.80%) as a brown solid, ¹H NMR (300 MHz, DMSO-d₆) δppm 2.39 (s, 3H), 3.34 (s, 3H), 7.42 (d, J=1.89 Hz, 1H), 7.51 (d, J=1.89Hz, 1H), 8.30 (s, 1H), 9.28 (s, 1H), 9.93 (s, 1H). LCMS: (Method-1)retention time: 0.84 min, [M+1]: 258.4.

Intermediate 83: 6-(4-methyl-1H-imidazol-1-yl)pyridazine-3-carbaldehyde

Intermediate 83A: ethyl6-(4-methyl-1H-imidazol-1-yl)pyridazine-3-carboxylate

Intermediate 83A was prepared (0.18 g, 72.00%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from4-methyl-1H-imidazole (0.11 g, 1.34 mmol) and ethyl6-chloropyridazine-3-carboxylate (0.20 g, 1.07 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.38 (t, J=7.12 Hz, 3H), 2.22 (d, J=0.94 Hz, 3H),4.41-4.47 (m, 2H), 7.86 (t, J=1.19 Hz, 1H), 8.28 (d, J=9.20 Hz, 1H),8.30 (d, J=8.80 Hz, 1H), 8.64 (d, J=1.32 Hz, 1H). LCMS: The compound didnot ionize well.

Intermediate 83B: (6-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)methanol

To a solution of Intermediate 83A (0.10 g, 0.43 mmol) in THE (5 mL) wasadded sodium borohydride (0.17 g, 0.43 mmol) at ambient temperature.MeOH (0.2 mL) was added dropwise and resulting reaction mixture wasstirred at ambient temperature for 2 h. The reaction was quenched withsaturated ammonium chloride solution, concentrated to dryness, dilutedwith water (10 mL) and extracted with DCM (2×25 mL). The combinedorganic layer was washed with brine (10 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure to obtain Intermediate 83B(0.05 g, 61.00%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H), 4.77 (d,J=5.52 Hz, 2H), 5.69 (t, J=5.95 Hz, 1H), 7.76 (s, 1H), 7.89 (d, J=9.07Hz, 1H), 8.13 (d, J=9.11 Hz, 1H), 8.51 (s, 1H). LCMS: The compound didnot ionize well.

Intermediate 83

Intermediate 83 was prepared (0.04 g, 85.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 83B (0.04 g, 0.21 mmol). LCMS: The compound did not ionizewell. The compound was taken directly to the subsequent step withoutfurther purification or characterization.

Intermediate 84: 6-(3-formylpyrrolidin-1-yl)-4-methoxynicotinonitrile

Intermediate 84A: 6-(3-(hydroxymethyl)pyrrolidin-1-yl)-4-methoxynicotinonitrile

Intermediate 84A was prepared (0.30 g, 68.00%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from6-bromo-4-methoxynicotinonitrile (0.40 g, 1.88 mmol) andpyrrolidin-3-ylmethanol (0.19 g, 1.88 mmol). LCMS (Method-L): retentiontime 1.26 min, [M+H] 234.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.90-1.92(m, 1H), 2.01-2.10 (m, 1H), 2.32-2.35 (m, 1H), 2.39-2.47 (m, 2H),2.52-2.54 (m, 3H), 3.37-3.49 (m, 1H), 3.92 (s, 3H) 4.73-4.78 (m, 1H),6.00 (s, 1H), 8.26 (s, 1H).

Intermediate 84

Intermediate 84 was prepared (0.05 g, crude), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 84A (0.05 g, 0.214 mmol) and Dess-Martin periodinane (0.09g, 0.214 mmol). LCMS (Method-L): retention time 0.47 min, [M+H] 232.1.The compound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate 85: 6-(3-formylpyrrolidin-1-yl)-4-methylnicotinonitrile

Intermediate 85A: 6-(3-(hydroxymethyl)pyrrolidin-1-yl)-4-methylnicotinonitrile

Intermediate 85A was prepared (0.30 g, 25.00%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from6-bromo-4-methylnicotinonitrile (0.40 g, 2.03 mmol) andpyrrolidin-3-ylmethanol (0.20 g, 2.03 mmol). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.70-1.80 (m, 1H), 1.97-2.07 (m, 1H), 2.37-2.45 (m, 1H), 2.55-2.58(m, 1H), 2.66-2.69 (m, 1H), 2.90 (m, 1H), 3.17-3.26 (m, 2H), 3.38 (s,1H), 3.50-3.60 (m, 2H), 4.74 (t, J=4.98 Hz, 1H), 6.46 (s, 1H), 7.95-7.97(m, 1H), 8.37 (s, 1H). LCMS (Method-L): retention time 1.30 min, [M+H]218.2.

Intermediate 85

Intermediate 85 was prepared (0.50 g, 68.10%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 85A (0.05 g, 0.230 mmol) and Dess-Martin periodinane (0.10g, 0.230 mmol). LCMS: The compound did not ionize well. The compound wastaken directly to the subsequent step without further purification orcharacterization.

Intermediate 86:6-(4-formyl-2-oxopyrrolidin-1-yl)-4-methylnicotinonitrile

Intermediate 86A: methyl1-(5-cyano-4-methylpyridin-2-yl)-5-oxopyrrolidine-3-carboxylate

Intermediate 86A was prepared (0.50 g, 76.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 15C andstarting from 6-bromo-4-methylnicotinonitrile (0.50 g, 2.54 mmol) andmethyl 5-oxopyrrolidine-3-carboxylate (0.36 g, 2.54 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.45-2.55 (m, 4H), 2.82-3.00 (m, 2H), 3.43-3.52 (m,1H), 3.65-3.72 (m, 2H), 4.22 (m, 2H), 8.34 (s, 1H), 8.78 (s, 1H). LCMS(Method-L): retention time 1.03 min, [M+1] 260.1.

Intermediate 86B:6-(4-(hydroxymethyl)-2-oxopyrrolidin-1-yl)-4-methylnicotinonitrile

Intermediate 86B was prepared (0.10 g, 22.00%), by using a similarsynthetic protocol as that of Intermediate 60B and starting fromIntermediate 86A (0.50 g, 1.93 mmol) and NaBH₄ (0.18 g, 4.82 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.30-2.35 (m, 3H), 2.70-2.80 (m, 2H),3.37-3.45 (m, 3H), 3.75-3.85 (m, 1H), 4.00-4.10 (m, 1H), 4.80-4.90 (m,1H), 8.37 (s, 1H), 8.76 (s, 1H). LCMS (Method-O): retention time 0.75min, [M+H] 232.1.

Intermediate 86

Intermediate 86 was prepared (0.08 g, 68.10%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 86B (0.08 g, 0.346 mmol) and Dess-Martin periodinane (0.15g, 0.346 mmol). LCMS (Method-L): retention time 0.72 min, [M+H] 230.2.The compound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate87:6-(4-formyl-2-oxopyrrolidin-1-yl)-4-methoxynicotinonitrile

Intermediate 87A: methyl1-(5-cyano-4-methoxypyridin-2-yl)-5-oxopyrrolidine-3-carboxylate

Intermediate 87A was prepared (0.50 g, 59.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 15C andstarting from 6-bromo-4-methoxynicotinonitrile (0.50 g, 2.35 mmol) andmethyl 5-oxopyrrolidine-3-carboxylate (0.34 g, 2.35 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.82-3.00 (m, 2H), 3.43-3.52 (m, 1H), 3.70 (m, 2H),3.90 (s, 1H), 4.00 (s, 3H), 4.22-4.35 (m, 2H), 8.12 (s, 1H), 8.65 (s,1H). LCMS (Method-L): retention time 1.01 min, [M+H] 276.9.

Intermediate 87B:6-(4-(hydroxymethyl)-2-oxopyrrolidin-1-yl)-4-methoxynicotinonitrile

Intermediate 87B was prepared (0.20 g, 44.50%), by using a similarsynthetic protocol as that of Intermediate 60B and starting fromIntermediate 87A (0.50 g, 1.82 mmol) and NaBH₄ (0.17 g, 4.54 mmol). LCMS(Method-L): retention time 0.73 min, [M+H] 248.0. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 87

Intermediate 87 was prepared (0.15 g, 68.10%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 87B (0.18 g, 0.73 mmol) and Dess-Martin periodinane (0.31g, 0.73 mmol). LCMS (Method-L): retention time 0.71 min, [M+H] 246.1.The compound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate 88:6-(5-formyl-2-oxooxazolidin-3-yl)-4-methylnicotinonitrile

Intermediate 88A: 5-(hydroxymethyl) oxazolidin-2-one

Synthesized according to literature procedures (US2014/206677 A1, 2014).

Intermediate 88B:6-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)-4-methylnicotinonitrile

Intermediate 88B was prepared (0.35 g, 35.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 15C andstarting from Intermediate 88A (0.50 g, 4.27 mmol) and6-bromo-4-methylnicotinonitrile (0.72 g, 4.27 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.45 (s, 3H), 3.53-3.61 (m, 1H), 3.66-3.73 (m, 1H), 3.99(dd, J=10.38, 5.93 Hz, 1H), 4.15-4.23 (m, 1H), 4.72-4.79 (m, 1H), 5.22(t, J=5.21 Hz, 1H), 8.15 (s, 1H), 8.75 (s, 1H). LCMS (Method-L):retention time 0.82 min, [M+1] 234.2.

Intermediate 88

Intermediate 88 was prepared (0.16 g, 64.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 88B (0.25 g, 1.07 mmol) and Dess-martin periodinane (0.57g, 1.34 mmol). LCMS: The compound did not ionize well. The compound wastaken directly to the subsequent step without further purification orcharacterization.

Intermediate 89:1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 89 was prepared (0.40 g, 75.00%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from2-bromo-5-(methylsulfonyl)pyridine (0.50 g, 2.12 mmol) and1H-pyrazole-4-carbaldehyde (0.20 g, 2.12 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.43-3.90 (s, 3H), 8.20-8.22 (m, 2H), 8.40 (s, 1H),8.54-8.57 (m, 1H), 9.00-9.04 (m, 1H), 10.00 (s, 1H). LCMS (Method-L):retention time 0.76 min, [M+H] 252.1.

Intermediate90:2-(4-formyl-1H-imidazol-1-yl)-4-methylpyrimidine-5-carbonitrile

Intermediate 90 was prepared (0.05 g, 9.00%) as a pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 15C andstarting from Intermediate 43C (0.62 g, 3.12 mmol) and1H-imidazole-4-carbaldehyde (0.25 g, 2.60 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.70 (s, 3H), 8.80 (s, 2H), 9.30 (s, 1H), 9.80 (s, 1H).LCMS (Method-O): retention time 0.76 min, [M+H] 214.4.

Intermediate 91:6′-(methysulfony)-[2,3′-bipyridine]-5-carbaldehyde

Intermediate 91A:2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Intermediate 91A was prepared (0.05 g, crude), by using a similarsynthetic protocol as that of Intermediate 2B and starting from5-bromo-2-(methylsulfonyl)pyridine (0.05 g, 0.21 mmol) andbis(pinacolato)diboron (0.07 g, 0.26). LCMS (Method-O): retention time0.94 min, [M+H] 284.2. The compound was taken directly to the subsequentstep without further purification or characterization.

Intermediate 91

Intermediate 91 was prepared (0.30 g, 64%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 91A (0.50 g, 1.77 mmol) and6-bromonicotinaldehyde (0.33 g, 1.77 mmol). LCMS (Method-O): retentiontime 0.94 min, [M+H] 263.2. The compound was taken directly to thesubsequent step without further purification or characterization.

Intermediate 92:2-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methoxypyrimidine-5-carbonitrile

Intermediate 92A:2-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methoxypyrimidine-5-carbonitrile

Intermediate 92A was prepared (0.90 g, 65.70%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 42 andstarting from Intermediate 45A (1.00 g, 5.90 mmol) and Intermediate 28A(0.88 g, 8.85 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.18 (s, 3H), 4.69(d, J=5.84 Hz, 2H), 5.59 (t, J=5.87 Hz, 1H), 8.25 (s, 1H), 9.18 (s, 1H).LCMS (Method-O): retention time 0.60 min, [M+H] 233.2.

Intermediate 92

Intermediate 92 was prepared (0.02 g, crude), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 92A (0.03 g, 5.90 mmol) and Dess-martinperiodinane (0.06 g,0.129 mmol). LCMS: The compound did not ionize well. The compound wastaken directly to the subsequent step without further purification orcharacterization.

Intermediate 93:6-(4-formyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 93A: methyl1-(5-cyano-4-methoxypyridin-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

Intermediate 93A was prepared (4.20 g, 70.70%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 15C andstarting from 6-chloro-4-methoxynicotinonitrile (4.27 g, 25.3 mmol) andmethyl 2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (3.00 g, 21.11mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.79 (s, 3H), 4.03 (s, 3H), 7.9(s, 1H), 8.32 (s, 1H), 8.71 (s, 1H), (1 Exchangeable proton was notobserved). LCMS (Method-D): retention time 1.81 min, [M+1] 275.

Intermediate 93B: methyl1-(5-cyano-4-methoxypyridin-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

To a stirred solution of Intermediate 93A (2.00 g, 7.29 mmol) in DMF (5mL) was added Cs₂CO₃ (4.75 g, 14.59 mmol) followed by iodomethane (0.91mL, 14.6 mmol) and the reaction mixture was stirred at ambienttemperature for 12 h. DMF was evaporated under reduced pressure and themixture was diluted with water (50 mL). The solid precipitate wasfiltered and washed with water (50 mL), diethyl ether (50 mL) and driedunder vacuum to obtain Intermediate 93B (1.70 g, 81.00%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.44 (s, 3H), 3.82 (s, 3H), 4.04(s, 3H), 8.02 (s, 1H), 8.24 (s, 1H), 8.76 (s, 1H). LCMS (Method-D):retention time 2.34 min, [M+1] 289.2.

Intermediate 93C:6-(4-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 93C was prepared (0.85 g, 92.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 93B (1.00 g, 3.47 mmol) and NaBH₄ (0.26 g,6.94 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.24 (s, 3H), 4.01 (s, 3H),4.36 (br.s, 2H), 5.25 (br.s, 1H), 7.29 (s, 1H), 8.28 (s, 1H), 8.69 (s,1H). LCMS (Method-D): retention time 1.24 min, [M+1] 261.

Intermediate 93

Intermediate 93 was prepared (0.100 g, 50.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 93C (0.20 g, 0.76 mmol) and Dess-Martin periodinane (0.39g, 0.92 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.46 (s, 3H), 4.01 (s,3H), 8.25 (s, 1H), 8.54 (s, 1H), 8.81 (s, 1H), 9.52 (s, 1H). LCMS(Method-D): retention time 1.91 min, [M+1] 259.

Intermediate 94:6-(4-formyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 94A: methyl1-(5-cyano-4-methoxypyridin-2-yl)-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

Intermediate 94A was prepared (0.48 g, 41.00%) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 93B andstarting from Intermediate 93A (1.00 g, 3.65 mmol) and 2-iodopropane(1.24 g, 7.29 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45 (d, J=8.00 Hz,6H), 3.8 (s, 3H), 4.04 (s, 3H), 5.0 (t, J=8.00 Hz, 1H), 8.04 (s, 1H),8.23 (s, 1H), 8.76 (s, 1H). LCMS (Method-D): retention time 2.70 min,[M+1] 317.2.

Intermediate 94B:6-(4-(hydroxymethyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 94B was prepared (0.35 g, 96.00%) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 94A (0.40 g, 1.26 mmol) and NaBH₄ (0.10 g,2.53 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45 (d, J=8.00 Hz, 6H),4.01 (s, 3H), 4.26-4.35 (m, 3H), 5.25 (br.s, 1H), 7.28 (s, 1H), 8.28 (s,1H), 8.68 (s, 1H), LCMS (Method-): retention time 0.9 min, [M+1]289.2.

Intermediate 94

Intermediate 94 was prepared (0.25 g, 49.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 94B (0.38 g, 1.32 mmol) and Dess-Martin periodinane (0.67g, 1.58 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45 (d, J=8.00 Hz, 6H),4.01 (s, 3H), 5.0 (t, J=8.00 Hz, 1H), 8.25 (s, 1H), 8.61 (s, 1H), 8.87(s, 1H), 9.45 (s, 1H). LCMS (Method-D): retention time 2.3 min, [M+1]287.2.

Intermediate 95:3-methyl-1-(2-methylpyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carbaldehyde

Intermediate 95A: methyl1-(5-cyano-4-methoxypyridin-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

To a solution of methyl 2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate(1.50 g, 10.55 mmol) in DMF (30 mL) was added4-chloro-2-methylpyrimidine (1.63 g, 12.67 mmol) followed by Cs₂CO₃(6.88 g, 21.11 mmol) and the resulting reaction mixture was heated at100° C. for 4 h. The reaction mixture was cooled to ambient temperature,concentrated to dryness under reduced pressure and diluted with water(50 mL). The solid precipitate obtained was filtered and dried undervacuum to afford Intermediate 95A (1.20 g, 36.40%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.67 (s, 3H), 3.82 (s, 3H), 7.85 (s, 1H), 8.3 (d, 6.0 Hz,1H), 8.6 (d, 6.0 Hz, 1H), (1 Exchangeable proton was not observed). LCMS(Method-D): retention time 1.06 min, [M+1] 235.2.

Intermediate 95B: methyl3-methyl-1-(2-methylpyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

Intermediate 95B was prepared (0.50 g, 47.00%), by using a similarsynthetic protocol as that of Intermediate 93B and starting fromIntermediate 95A (1.00 g, 4.27 mmol) and 2-iodomethane (0.5 mL, 8.54mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.63 (s, 3H), 3.42 (s, 3H), 3.82(s, 3H), 8.04 (s, 1H), 8.15 (d, J=6.00 Hz, 1H), 8.75 (d, J=6.00 Hz, 1H).LCMS (Method-D): retention time 1.54 min, [M+1] 249.2.

Intermediate 95C:4-(hydroxymethyl)-3-methyl-1-(2-methylpyrimidin-4-yl)-1,3-dihydro-2H-imidazol-2-one

Intermediate 95C was prepared (0.20 g, 45.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 95B (0.50 g, 2.014 mmol) and NaBH₄ (0.15 g,4.03 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.58 (s, 3H), 3.22 (s, 3H),4.36 (d, 5.2 Hz, 2H), 5.24 (s, 1H), 7.3 (s, 1H), 8.15 (d, J=6.00 Hz,1H), 8.65 (d, J=6.00 Hz, 1H). LCMS (Method-D): retention time 0.55 min,[M+1] 221.5.

Intermediate 95

Intermediate 95 was prepared (0.13 g, 64.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 95C (0.20 g, 0.91 mmol) and Dess-Martin periodinane (0.46g, 1.09 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.66 (s, 3H), 3.45 (s,3H), 8.2 (d, 6.0 Hz, 1H), 8.54 (s, 1H), 8.81 (d, 6.0 Hz, 1H), 9.54 (s,1H). LCMS (Method-D): retention time 1.08 min, [M+1] 219.2.

Intermediate 96-I:5-((2R,6S)-4-((6-bromopyridin-3-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

To a stirred solution of 6-bromonicotinaldehyde (0.300 g, 1.61 mmol) inTHE (20 mL) was added Intermediate 51-I (0.44 g, 1.77 mmol) and thereaction mixture was continued to stir at ambient temperature for 10minutes. Sodium triacetoxyborohydride (0.68 g, 3.23 mmol) was added andstirring was continued for 48 h. The reaction mixture was diluted withaq NaHCO₃ (30 mL) and extracted with ethyl acetate (2×40 mL). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-40 g, 65-70%EtOAc/n-Hexane) to afford Intermediate 96-I (0.32 g, 47.00%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.01 (d, J=6.02 Hz, 3H), 1.70-1.79 (m, 2H),2.24 (s, 3H), 2.72 (t, J=8.78 Hz, 2H), 2.96 (td, J=6.53, 3.01 Hz, 1H),3.52 (s, 2H), 4.15 (dd, J=10.04, 2.51 Hz, 1H), 5.38 (s, 2H), 7.59-7.67(m, 2H), 7.68-7.72 (m, 1H), 7.80 (d, J=8.03 Hz, 1H), 8.31 (d, J=2.01 Hz,1H), (1 exchangeable proton not observed). LCMS (Method-D): retentiontime 1.95 min, [M+H] 417.

Intermediate97:5-((2R,6S)-4-((1H-1,2,4-triazol-3-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 97A: Methyl 1-trityl-1H-1,2,4-triazole-3-carboxylate

Intermediate 97A was prepared (8.00 g, 45.10%), by using a similarsynthetic protocol as that of Intermediate 75A and starting from1H-1,2,4-triazole-3-carboxylate (5.00 g, 39.30 mmol) and trityl chloride(13.16 g, 47.20 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.83 (s, 3H),7.05-7.09 (m, 5H), 7.40-7.42 (m, 10H), 8.38 (s, 1H), LCMS: The compounddid not ionize well.

Intermediate 97B: (1-trityl-H-1,2,4-triazol-3-yl)methanol

Intermediate 97B was prepared (1.00 g, 50.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 97A (2.00 g, 5.41 mmol) and NaBH₄ (0.60 g,16.24 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.45 (d, J=6.02 Hz, 2H),5.30 (t, J=6.02 Hz, 1H), 7.05-7.09 (m, 5H), 7.37-7.42 (m, 10H), 8.04 (s,1H). LCMS: The compound did not ionize well.

Intermediate 97C: 1-trityl-1H-1,2,4-triazole-3-carbaldehyde

Intermediate 97C was prepared (0.75 g, 90.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 97B (0.80 g, 2.34 mmol) and Dess-Martin periodinane (2.00g, 4.70 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.05-7.09 (m, 5H),7.40-7.42 (m, 10H), 8.38 (s, 1H), 9.45 (s, 1H). LCMS: The compound didnot ionize well.

Intermediate 97D:4-methyl-5-((2R,6S)-6-methyl-4-((1-trityl-1H-1,2,4-triazol-3-yl)methyl)piperazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 97D was prepared (0.90 g, 71.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 96-I andstarting from Intermediate 97C (0.75 g, 2.21 mmol) and Intermediate 51-I(0.60 g, 2.43 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98 (d, J=6.28 Hz,3H), 1.69-1.86 (m, 2H), 2.23 (s, 3H), 2.68-2.78 (m, 2H), 2.90 (br. s.,1H), 3.60 (s, 2H), 4.10 (d, J=7.10 Hz, 1H), 5.39 (s, 2H), 7.01-7.07 (m,6H), 7.31-7.38 (m, 9H), 7.64-7.69 (m, 1H), 7.75-7.79 (m, 1H), 8.04 (s,1H), (1 exchangeable proton not observed). LCMS (Method-D): retentiontime 4.045 min, [M+H] 570.4.

Intermediate 97

Intermediate 97 was prepared (0.18 g, 28.20%), by using a similarsynthetic protocol as that of Intermediate 4C and starting fromIntermediate 97_(D) (1.00 g, 1.75 mmol) and 4M HCl in dioxane (0.88 ml,3.51 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00 (d, J=6.28 Hz, 3H),1.72-1.85 (m, 2H), 2.25 (s, 3H), 2.76 (d, J=10.24 Hz, 2H), 2.94 (br. s.,1H), 3.62 (s, 2H), 4.14 (d, J=9.25 Hz, 1H), 5.38 (s, 2H), 7.65 (d,J=8.09 Hz, 1H), 7.78 (d, J=8.26 Hz, 1H), 8.12 (br. s., 1H), 13.9 (br.s., 1H). (1 exchangeable proton not observed). LCMS (Method-D):retention time 0.63 min, [M+H] 328.2.

Intermediate 98:6-(4-formyl-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 98 was prepared (0.30 g, 25.00%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from1H-imidazole-4-carbaldehyde (0.50 g, 5.20 mmol) and6-chloro-4-methoxynicotinonitrile (1.05 g, 6.24 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.13 (s, 3H), 7.81 (s, 1H), 8.83 (s, 2H), 8.95 (d, J=1.19Hz, 1H), 9.87 (s, 1H). LCMS (Method-L): retention time 0.75 min, [M+H]229.1.

Intermediate 99:6-(4-formyl-5-methyl-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 99A: Ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate

Intermediate 99A was prepared (5.20 g, 35.70%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 28A andstarting from ethyl but-2-ynoate (10.00 g, 89.00 mmol) andazidotrimethylsilane (17.76 mL, 134.00 mmol). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.31 (t, J=7.09 Hz, 3H), 2.51 (br. s., 3H), 4.30 (q, J=6.93 Hz,2H), 15.36 (br. s., 1H). LCMS (Method-D): retention time 0.68 min, [M+H]156.2.

Intermediate 99B: ethyl1-(5-cyano-4-methylpyridin-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylateand Intermediate 99C: ethyl2-(5-cyano-4-methylpyridin-2-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylate

Intermediate 99B and 99C was prepared by using a similar syntheticprotocol as that of Intermediate 20 and starting from Intermediate 99A(5.00 g, 32.20 mmol) and 6-bromo-4-methylnicotinonitrile (7.62 g, 38.70mmol). The regioisomers were separated into individual isomers by HPLC[YMC trait (250×20 mm) 5 micron; Solvent A: 10 mM NaHCO₃; Solvent B:Acetonitrile:MeOH (1:1), Gradient: 50-100% B over 15 minutes, Flow: 20mL/min, UV: 254]. First eluted compound (retention time 10.42 min),designated as Intermediate 99B, was obtained (0.50 g, 5.50%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.38 (m, 3H), 2.67(s, 3H), 2.83 (s, 3H), 4.39 (q, J=7.03 Hz, 2H), 8.20 (s, 1H), 9.07 (s,1H). LCMS (Method-D): retention time 2.37 min, [M+H]272.0. Second elutedcompound (retention time 11.65 min), designated as Intermediate 99C, wasobtained (3.10 g, 28.40%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.33-1.38 (m, 3H), 2.56 (s, 3H), 2.64 (s, 3H), 4.39 (q,J=7.03 Hz, 2H), 8.18 (s, 1H), 8.97 (s, 1H). LCMS (Method-D): retentiontime 2.45 min, [M+H] 272.0.

Intermediate 99D:6-(4-(hydroxymethyl)-5-methyl-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 99D was prepared (0.25 g, 48.80%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 99C (0.60 g, 2.21 mmol) and NaBH₄ (0.17 g,4.43 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.39 (s, 3H), 2.60 (s, 3H),4.62 (d, J=5.52 Hz, 2H), 5.39 (t, J=5.77 Hz, 1H), 8.04 (s, 1H), 8.89 (s,1H). LCMS (Method-D): retention time 1.16 min, [M+H] 230.0.

Intermediate 99

Intermediate 99 was prepared (0.25 g, 48.80%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 99_(D) (0.20 g, 0.87 mmol) and Dess-Martin periodinane(0.74 g, 1.75 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.58 (s, 3H), 2.66(s, 3H), 8.24 (s, 1H), 9.01 (s, 1H), 10.23 (s, 1H). LCMS (Method-D):retention time 1.95 min, [M−H] 226.1.

Intermediate 100:6-(4-formyl-5-methyl-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Intermediate 100A:6-(4-(hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Intermediate 100A was prepared (0.28 g, 71.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 99B (0.40 g, 1.47 mmol) and NaBH₄ (0.11 g,2.95 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.59 (s, 3H), 2.64 (s, 3H),4.55 (d, J=5.52 Hz, 2H), 5.19 (t, J=5.77 Hz, 1H), 8.16 (s, 1H), 9.0 (s,1H). LCMS (Method-D): retention time 1.22 min, [M+H] 230.2.

Intermediate 100

Intermediate 100 was prepared (0.20 g, 56.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 100A (0.25 g, 1.09 mmol) and Dess-Martin periodinane (0.70g, 1.64 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.66 (s, 3H), 2.72 (s,3H), 8.24 (s, 1H), 9.01 (s, 1H), 10.28 (s, 1H). LCMS (Method-D):retention time 1.97 min, [M+H] 228.2.

Intermediate 101:1-(2-(5-cyano-4-methylpyridin-2-yl)-2H-1,2,3-triazol-4-yl)ethylmethanesulfonate

Intermediate 101A:6-(4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 101A was prepared (0.74 g, 80.00%) as an yellow solid, byusing a similar synthetic protocol as that of Intermediate 72A andstarting from Intermediate 28 (0.80 g, 3.75 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.48 (d, J=6.53 Hz, 3H), 2.62 (s, 3H), 4.93-5.00 (m, 1H),5.58 (d, J=5.02 Hz, 1H), 8.10-8.11 (m, 1H), 8.17 (s, 1H), 8.93 (s, 1H).LCMS (Method-D): retention time 1.05 min, [M+H] 230.0.

Intermediate 101

Intermediate 101A was prepared (0.20 g, 56.70%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 59 andstarting from Intermediate 101A (0.25 g, 1.09 mmol) and mesyl chloride(0.102 mL, 1.31 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78 (d, J=6.80Hz, 3H), 2.64 (s, 3H), 3.28 (s, 3H), 6.03 (q, J=6.80 Hz, 1H), 8.16 (s,1H), 8.40 (s, 1H), 8.97 (s, 1H). LCMS (Method-D): retention time 1.56min, [M+H] 308.2.

Intermediate 102: 2-methyl-6-(trimethylstannyl)pyridazin-3(2H)-one

Intermediate 102A: 6-chloro-2-methylpyridazin-3(2H)-one

To a stirring solution of 6-chloropyridazin-3(2H)-one (0.35 g, 2.68mmol) in DMF (10 mL) was added K₂CO₃ (0.93 g, 6.70 mmol) followed bymethyliodide (0.20 mL, 3.22 mmol) and stirred at ambient temperature for1 h. The resulting reaction mixture was diluted with water (30 mL) andextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 102A (0.25 g,56.10%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.75 (s,3H), 6.92 (d, J=9.76 Hz, 1H), 7.19 (d, J=9.76 Hz, 1H). LCMS (Method-D):retention time 0.66 min, [M+1] 145.2.

Intermediate 102

Intermediate 102 was prepared (0.15 g, crude), by using a similarsynthetic protocol as that of Intermediate 23A and starting fromIntermediate 102A (0.10 g, 0.69 mmol) and1,1,1,2,2,2-hexamethyldistannane (0.16 mL, 0.76 mmol). LCMS (Method-O):retention time 1.30 min, [M+1] 275.2. The compound was taken directly tothe subsequent step without further purification or characterization.

Intermediate 103:5-(5-(hydroxymethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one(Diastereomer-I

Intermediate 103A:2-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloropyrazine

To a stirred solution of (5-chloropyrazin-2-yl)methanol (0.50 g, 3.46mmol) in DCM (10 mL) was added imidazole (0.94 g, 13.84 mmol) followedby TBDMS-Cl (1.04 g, 6.92 mmol) and stirring continued at ambienttemperature for 12 h. The resulting reaction mixture was diluted withwater (40 mL) and extracted with DCM (2×40 mL). The combined organiclayers were dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography(Redisep-24 g, 5-10% EtOAc/n-hexane) to obtain Intermediate 103A (0.85g, 89.00%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.11 (s, 6H), 0.91 (s, 9H),4.84 (s, 2H), 8.50 (s, 1H), 8.75 (d, J=1.00 Hz, 1H). LCMS (Method-D):retention time 3.69 min, [M+H] 259.

Intermediate 103B:5-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 103B (1.80 g, 44.0%) was prepared as a brown solid, byusing a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 103A (2.83 g, 10.94 mmol) and Intermediate 2B(3.00 g, 10.94 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.15 (s, 6H), 0.94(s, 9H), 2.33 (s, 3H), 4.93 (s, 2H), 5.50 (s, 2H), 7.71 (d, J=8.00 Hz,1H), 7.8 (d, J=8.00 Hz, 1H), 8.81 (s, 1H), 8.84 (d, J=1.51 Hz, 1H). LCMS(Method-D): retention time 3.78 min, [M+H] 371.2.

Intermediate 103C and 103D:5-(5-(((tert-butyldimethylsilyl)oxy)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 103C and 103D was prepared by using a similar syntheticprotocol as that of Intermediate 2-I and 2-II and starting fromIntermediate 103B (2.30 g, 6.21 mmol). The two diastereomers wereseparated by column chromatography (Redisep-40 g, 5-10% EtOAc/n-hexane).First eluted compound designated as Intermediate 103C, was obtained(0.35 g, 30.40%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.06(s, 6H), 0.89 (s, 9H), 2.29 (s, 3H), 2.43 (br. s., 2H), 2.73-2.75 (m,1H), 2.90-2.92 (m, 1H), 3.02-3.07 (m, 1H), 3.43-3.54 (m, 2H), 3.88-3.93(m, 1H), 5.38 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.76 (d, J=8.03 Hz, 1H),(2 Exchangeable protons not observed). LCMS (Method-D) retention time2.34 min, [M+H] 377.3. Second eluted compound designated as Intermediate103_(D), was obtained (0.08 g, 7.00%) as a colorless syrup. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.08 (s, 6H), 0.89 (s, 9H), 2.26 (s, 1H), 2.29 (s,3H), 2.55-2.68 (m, 1H), 2.85-2.98 (m, 2H), 3.78 (dd, J=9.54, 7.03 Hz,1H), 3.90-3.99 (m, 3H), 5.37 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.84 (d,J=8.03 Hz, 1H), (2 Exchangeable protons not observed). LCMS (Method-D)retention time 2.61 min, [M+H]377.3.

Intermediate 103

To a stirred solution of Intermediate 103C (0.15 g, 0.40 mmol) in DCM (5mL) was added, 1.4 M HCl in dioxane (0.011 mL, 0.362 mmol) and thereaction mixture was stirred at ambient temperature for 16 h. Thereaction mixture was concentrated to dryness under reduced pressure andthe residue was washed with diethylether (2×10 mL). The solid obtainedwas redissolved into ACN (3 mL) and K₂CO₃ (0.30 g) was added and theresulting mixture was stirred at ambient temperature for 3 h. The solidprecipitate was filtered and dried under vacuum to obtain Intermediate103 (0.08 g, 79.00%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.18-2.23 (m, 2H), 2.30 (s, 3H), 2.86-2.92 (m, 1H), 2.99-3.04 (m, 1H),3.27-3.31 (m, 3H), 3.89-3.93 (m, 1H), 4.55 (s, 1H), 5.39 (s, 2H), 7.65(d, J=8.07 Hz, 1H), 7.79 (d, J=8.56 Hz, 1H). (2 Exchangeable protons notobserved). LCMS (Method-D): retention time 0.55 min, [M+H] 263.2.

Intermediate 104:6-(4-(chloromethyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 104A:6-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 104A was prepared (0.30 g, 41%) as a pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 6 (0.50 g, 2.36 mmol) and NaBH₄ (0.09 g, 2.36mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.6 (s, 3H), 4.45 (d, J=5.6 Hz,2H), 5.1 (t, J=5.60 Hz, 1H), 7.86 (s, 1H), 7.99 (s, 1H), 8.5 (s, 1H),8.85 (s, 1H). LCMS (Method-D): retention time 1.33 min, [M+H]215.2.

Intermediate 104

Intermediate 104 was prepared (0.02 g, 69.00%), by using a similarsynthetic protocol as that of Intermediate 59 and starting fromIntermediate 104A (0.20 g, 0.93 mmol) and mesyl chloride (0.087 mL,1.120 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.6 (s, 3H), 4.8 (s, 2H),7.86 (s, 1H), 7.99 (s, 1H), 8.5 (s, 1H), 8.85 (s, 1H). LCMS (Method-L):retention time 1.24 min, [M+2] 234.9.

Intermediate 105-I and 105-II:5-(6-(2-hydroxypropan-2-yl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 105A: 2-(6-chloropyrazin-2-yl)propan-2-ol

To a stirring solution of methyl 6-chloropyrazine-2-carboxylate (2.50 g,14.49 mmol) in THE (50 mL) was added methylmagnesium bromide 3M indiethyl ether (12.07 mL, 36.2 mmol) at 0° C. The resulting mixture wasstirred at ambient temperature for 30 minutes. The reaction mixture wasdiluted with saturated NH₄Cl (100 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography (Redisep-24g, 0.40% EtOAc/n-hexane) to obtain Intermediate 105A (0.70 g, 28.00%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44 (s, 6H), 5.58 (br, s 1H), 8.66 (s,1H), 8.86 (s, 1H). LCMS: The compound did not ionize well.

Intermediate 105B:5-(6-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 105B was prepared (0.65 g, 78.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 105A (0.50 g, 2.92 mmol) and Intermediate 2B(0.80 g, 2.92 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (s, 6H),2.27-2.37 (m, 3H), 5.50 (s, 2H), 5.54 (s, 1H), 7.71-7.77 (m, 1H),7.79-7.85 (m, 1H), 8.77 (s, 1H), 8.95 (s, 1H). LCMS (Method-1):retention time 0.82 min, [M+H] 285.1.

Intermediate 105-I and 105-II

Intermediate 105-I and 105-II was prepared by using a similar syntheticprotocol as that of Intermediate 2-I and 2-I and starting fromIntermediate 105B (0.65 g, 2.28 mmol). The crude residue was purified bypreparative HPLC [Lux-cellulose C5 (250×30 mm) 5 micron; Solvent: 0.1%DEA+ACN:IPA (90:10), Gradient: 100% over 17 min, Flow: 30 mL/min, UV:254] to obtain pure recemates. The racemic mixture was separated intotwo individual enantiomers by supercritical fluid chromatography (SFC)[Chiralpak ADH (250×21 mm) 5 micron; 0.2% NH₄OH in MeOH, Flow: 60.0g/min. Temperature: 30° C., UV: 235 nm]. First eluted compound(retention time 5.16 min), designated as Intermediate 105-I, wasobtained (0.04 g, 5.27%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.13 (d, J=3.01 Hz, 6H), 2.23-2.34 (m, 6H), 2.55-2.72 (m,2H), 2.84 (t, J=9.79 Hz, 2H), 4.03 (d, J=9.54 Hz, 1H), 4.34 (s, 1H),5.39 (s, 2H), 7.68 (d, J=8.03 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H). LCMS(Method-D): retention time 0.62 min, [M+H] 291.2. Chiral purity(Method-XII): retention time 3.89 min, 100% ee. Second eluted compound(retention time 6.50 min), designated as Intermediate 105-I, wasobtained (0.04 g, 5.27%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.13 (d, J=3.01 Hz, 6H), 2.20-2.36 (m, 6H), 2.57-2.70 (m,2H), 2.84 (t, J=8.53 Hz, 2H), 4.03 (d, J=7.03 Hz, 1H), 4.34 (s, 1H),5.39 (s, 2H), 7.68 (d, J=7.53 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H). LCMS(Method-D): retention time 0.613 min, [M+H] 291.2. Chiral purity(Method-A): retention time 4.94 min, 100% ee.

Intermediate 106:5-(4-hydroxypyrrolidin-3-yl)-4-methylisobenzofuran-1(3H)-onehydrochloride (Diastereomer-I

Intermediate 106A:tert-butyl3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-oxopyrrolidine-1-carboxylate

Intermediate 106A was prepared (0.80 g, 10.96°) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 4A andstarting from Intermediate 2A (5.00 g, 22.02 mmol) and tert-butyl3-oxopyrrolidine-1-carboxylate (6.93 g, 37.4 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.27-1.59 (m, 9H), 2.15-2.30 (m, 3H), 3.62 (dd, J=10.79,8.78 Hz, 1H), 3.80-3.91 (m, 1H), 3.94-4.09 (m, 1H), 4.22-4.33 (m, 1H),4.37-4.48 (m, 1H), 5.32-5.41 (m, 2H), 7.38 (d, J=8.03 Hz, 1H), 7.58 (d,J=8.03 Hz, 1H). LCMS (Method-1): retention time 1.11 min, [M−H] 330.3.

Intermediate 106B and 106C: tert-butyl3-hydroxy-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidine-1-carboxylate

Intermediate 106B and 106C was prepared by using a similar syntheticprotocol as that of Intermediate 60B and starting from Intermediate 106A(0.80 g, 2.41 mmol) and NaBH₄ (0.18 g, 4.83 mmol). The two diastereomerswere separated by supercritical fluid chromatography (SFC) [ChiralpakAD-H (250×21 mm) 5 micron; 0.2% NH₄OH in MeOH, Flow: 70.0 g/min.Temperature: 30° C., UV: 240 nm]. First eluted compound (retention time4.08 min), designated as Intermediate 106B, was obtained (0.29 g,36.00%) as an off-white solid. ¹H NMR: Showed diastereomeric mixture.LCMS (Method-D): retention time 1.96 min and 2.02 min, [(M−100)+H]334.1. Chiral purity (Method-XII): retention time 2.44 min, 100% ee.Second eluted compound (retention time 7.31 min), designated asIntermediate 106C, was obtained (0.30 g, 37.30%) as an off-white solid.¹H NMR: Showed diastereomeric mixture. LCMS (Method-D): retention time1.95 min and 2.02 min, [(M−100)+H] 334.1. Chiral purity (Method-M):retention time 4.55 min, 100% ee.

Intermediate 106

Intermediate 106 was prepared (0.20 g, 99.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 52-I andstarting from Intermediate 106B (0.25 g, 0.75 mmol). LCMS (Method-1):retention time 0.46 min, [M+H] 234.1. The compound was taken directly tothe subsequent step without further purification or characterization.

Intermediate 107:5-(4-fluoropyrrolidin-3-yl)-4-methylisobenzofuran-1(3H)-onehydrochloride

Intermediate 107A:tert-butyl3-fluoro-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidine-1-carboxylate

Intermediate 107 was prepared (0.22 g, crude), by using a similarsynthetic protocol as that of Intermediate 4B and starting fromIntermediate 106A (0.35 g, 1.05 mmol) and DAST (0.69 mL, 5.25 mmol).LCMS: The compound did not ionize well. The compound was taken directlyto the subsequent step without further purification or characterization.

Intermediate 107

Intermediate 107 was prepared (0.18 g, 99.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 52-I andstarting from Intermediate 108A (0.25 g, 0.75 mmol).

LCMS (Method-I): retention time 0.47 min and 0.57 min, [M+H] 216.5. Thecompound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate 108:6-(4-formyl-1H-pyrazol-1-yl)-4-(trifluoromethyl)nicotinonitrile

Intermediate 108A: 6-chloro-4-(trifluoromethyl)nicotinonitrile

Synthesized according to literature procedures (WO2006/68618 A1, 2006).

Intermediate 108

Intermediate 108 was prepared (0.40 g, 48.10%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from Intermediate 107A (0.77 g, 3.75 mmol) and1H-pyrazole-4-carbaldehyde (0.30 g, 3.12 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.35 (s, 1H), 8.47 (s, 1H), 9.37 (s, 1H), 9.49 (s, 1H),10.02 (s, 1H). LCMS: The compound did not ionize well.

Intermediate 109-I:(5R,8aR)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)hexahydro-_3H-oxazolo[3,4-a]pyrazin-3-one

Intermediate 109A-I: tert-butyl(5R,8aR)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-oxotetrahydro-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate

To a stirring solution of Intermediate 38D-I (0.75 g, 2.07 mmol) in THE(20 mL) was added K₂CO₃ (0.86 g, 6.21 mmol) followed by triphosgene(0.61 g, 2.07 mmol) and the resulting reaction mixture was heated at 70°C. for 16 h. The reaction mixture was cooled to ambient temperature,diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL).The combined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-12 g, 50%EtOAc/n-hexane) to obtain Intermediate 109A-I (0.700 g, 87.00%) as apale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.23 (m, 9H),2.32 (s, 3H), 2.96 (br. s., 1H), 3.49 (dd, J=12.00, 4.00 Hz, 1H),4.01-4.11 (m, 3H), 4.44-4.50 (m, 1H), 4.78-4.80 (m, 1H), 5.15 (d, J=5.00Hz, 1H), 5.35-5.41 (m, 2H), 7.58 (d, J=6.50 Hz, 1H), 7.68 (d, J=6.50 Hz,1H). LCMS (Method-I): retention time 1.34 min, [M+H] 389.2.

Intermediate 109-I

Intermediate 109-I was prepared (0.40 g, 77.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 4C andstarting from Intermediate 109A-I (0.70 g, 1.80 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.29-2.38 (m, 3H), 3.00-3.23 (m, 2H), 3.34-3.44 (m, 1H),3.60 (br. s., 2H), 3.90-4.07 (m, 1H), 4.25-4.37 (m, 1H), 4.43-4.54 (m,1H), 5.10 (dd, J=11.55, 3.51 Hz, 1H), 5.35-5.52 (m, 2H), 7.61-7.67 (m,1H), 7.67-7.76 (m, 1H). LCMS (Method-1): retention time 0.5 min, [M+H]289.2.

Intermediate 110: 6-(5-formylisoxazol-3-yl)-4-methylnicotinonitrile

Intermediate 110A: 6-formyl-4-methylnicotinonitrile

To a stirred solution of 6-bromo-4-methylnicotinonitrile (2.00 g, 10.15mmol) in DMF (15 mL) was added solid Na₂CO₃ (1.08 g, 10.15 mmol) atambient temperature, under nitrogen atmosphere. The resulting reactionmixture was degassed with nitrogen gas for minutes and added tert-butylisocyanide (1.01 g, 12.18 mmol), 1,4-bis(diphenylphosphino)butane (0.13g, 0.30 mmol), palladium(II) acetate (0.07 g, 0.30 mmol) andtriethylsilane (1.18 g, 10.15 mmol). The reaction mixture was heated to65° C. for 5 h and cooled to ambient temperature. The reaction mixturewas filtered through Celite® and the filtrate was diluted with water(100 mL) and extracted with ethylacetate (2×100 mL). The combinedorganic layers were washed with brine (30 mL), dried over anhydroussodium sulfate and evaporated under reduced pressure. To obtainIntermediate 110A (0.30 g, 20.00%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.61(s, 3H), 8.01 (s, 1H), 9.15 (s, 1H), 10.01 (s, 1H). LCMS (Method-D):retention time 2.45 min, [M+H] 147.0. The compound was taken directly tothe subsequent step without further purification or characterization.

Intermediate 110B: (E)-6-((hydroxyimino)methyl)-4-methylnicotinonitrile

To a stirred solution of Intermediate 110A (0.50 g, 3.00 mmol) in EtOH(10 mL) was added hydroxylamine hydrochloride (0.26 g, 3.70 mmol) andsodium acetate (0.30 g, 3.70 mmol) at ambient temperature, under anitrogen atmosphere. The resulting suspension was heated to 75° C. for25 minutes. The reaction mixture was cooled to ambient temperature,diluted with water (60 mL) and extracted with ethyl acetate (2×100 mL).The combined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was slurried with DCM (5 mL) and the solid was collected bysuction filtration and dried under vacuum to obtain Intermediate 110B(0.30 g, 60.00%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.52(s, 3H), 7.86 (s, 1H), 8.12 (s, 1H), 8.92 (s, 1H), 12.13 (s, 1H). LCMS(Method H): retention time 0.77 min, [M+H] 162.2.

Intermediate 110C:6-(5-(hydroxymethyl)isoxazol-3-yl)-4-methylnicotinonitrile

To a solution of Intermediate 110B (0.20 g, 1.24 mmol) in DMF (10 mL)was added N-chlorosuccinimide (0.17 mg, 1.24 mmol) and the resultingreaction mixture was heated at 50° C. for 1 h. The reaction mixture wascooled to ambient temperature and prop-2-yn-1-ol (0.07 g, 1.24 mmol)followed by TEA (0.17 mL, 1.24 mmol) were added and stirred for 3 h. Thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (3×30 mL). The combined organic layers were washed with brine(20 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography(Redisep-12 g, 30% EtOAc/n-hexane) to obtain Intermediate 110C (0.08 g,30.00%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.55-2.63(m, 3H), 4.67 (dd, J=6.02, 1.00 Hz, 2H), 5.76 (t, J=6.02 Hz, 1H), 6.95(s, 1H), 8.16 (s, 1H), 9.06 (s, 1H). LCMS (Method-I): retention time 0.9min, [M+H]216.0.

Intermediate 110

Intermediate 110 was prepared (0.75 g, 95.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 110C (0.08 g, 0.37 mmol) and

Dess-Martin periodinane (0.24 g, 0.56 mmol). ¹H NMR (400 MHz, DMSO-d₆) δppm 2.50-2.51 (m, 3H), 7.92 (s, 1H), 8.27 (s, 1H), 9.12 (s, 1H), 9.99(s, 1H). LCMS: The compound did not ionize well.

Intermediate 111:6-(4-formyl-1H-imidazol-1-yl)-2,4-dimethylnicotinonitrile

Intermediate 111 was prepared (0.08 g, 29.50%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 6-chloro-2,4-dimethylnicotinonitrile (0.20 g, 1.18 mmol)and 1H-imidazole-4-carbaldehyde (0.12 g, 1.12 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.55-2.61 (m, 3H), 2.73 (s, 3H), 7.98 (s, 1H), 8.76 (d,J=0.98 Hz, 1H), 8.81 (d, J=1.22 Hz, 1H), 9.88 (s, 1H). LCMS (Method-1):retention time 0.92 min, [M+1] 227.5.

Intermediate 112:6-(4-formyl-1H-1,2,3-triazol-1-yl)-2,4-dimethylnicotinonitrile

Intermediate 112A:6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-2,4-dimethylnicotinonitrileand Intermediate 112B:6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-2,4-dimethylnicotinonitrile

Intermediate 112A and Intermediate 112B was as prepared, by using asimilar synthetic protocol as that of Intermediate 20 and starting fromIntermediate 28A (1.00 g, 10.09 mmol) and6-chloro-2,4-dimethylnicotinonitrile (1.85 g, 11.10 mmol). First elutedcompound, designated as Intermediate 112A was obtained (0.30 g, 12.97%),as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.63 (s, 3H),2.74 (s, 3H), 4.64 (d, J=6.00 Hz, 2H), 5.37 (t, J=6.00 Hz, 1H), 8.12 (s,1H), 8.69 (s, 1H). LCMS (Method-1): retention time 0.77 min, [M+1]230.4. Second eluted compound, designated as Intermediate 112B wasobtained (0.32 g, 13.83%), as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.59 (s, 3H), 2.71 (s, 3H), 4.67 (d, J=6.00 Hz, 2H), 5.53(t, J=6.00 Hz, 1H), 7.95 (s, 1H), 8.16 (s, 1H). LCMS (Method-1):retention time 0.74 min, [M+1] 230.4.

Intermediate 112

Intermediate 112 was prepared (0.30 g, 66.20%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 112A (0.32 g, 1.40 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.65 (s, 3H), 2.76 (s, 3H), 8.21 (s, 1H), 9.56 (s, 1H),10.13 (s, 1H). LCMS (Method-1): retention time 0.98 min, [M−1] 228.4.

Intermediate 113:6-(4-formyl-2H-1,2,3-triazol-2-yl)-2,4-dimethylnicotinonitrile

Intermediate 113 was prepared (0.40 g, 86.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 112B (0.32 g, 1.40 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.64 (s, 3H), 2.76 (s, 3H), 8.11 (s, 1H), 8.77 (s, 1H),10.21 (s, 1H). LCMS (Method-1): retention time 0.93 min, [M+H] 228.4.

Intermediate 114:6-(4-formyl-1H-1,2,3-triazol-1-yl)-2-methoxy-4-methylnicotinonitrile

Intermediate 114A: 6-chloro-2-methoxy-4-methylnicotinonitrile andIntermediate 114B: 2-chloro-6-methoxy-4-methylnicotinonitrile

To a stirred solution of 2,6-dichloro-4-methylnicotinonitrile (15.00 g,80.00 mmol) in MeOH (100 mL) was added sodium methoxide (14.89 mL, 80.00mmol) and the reaction mixture was stirred at ambient temperature for 16h. The reaction mixture was diluted with water (300 mL) and extractedwith DCM (3×250 mL). The combined organic layers were washed with brine(200 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by SFC [Column: Luxcellulose-2 (50×250 mm) 5 micron; 10% of 0.2% DEA in IPA; total flow:150 g/min; UV: 220 nm] to obtain Intermediate 114A (5.50 g, 32.30%) asan off-white solid, (retention time: 6.3 min). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.46 (s, 3H), 3.99 (s, 3H), 7.27 (s, 1H). LCMS: (Method-1)retention time: 1.22 min, [M+1] 183.3. Intermediate 114B (6.50 g,40.40%) as an off-white solid, (retention time: 5.8 min). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.43 (s, 3H), 3.91 (s, 3H), 6.94 (s, 1H). LCMS(Method-1): retention time 1.29 min, [M+1]183.4.

Intermediate 114C:6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-2-methoxy-4-methylnicotinonitrileand Intermediate 114D:6-(4-(hydroxymethy)-1H-1,2,3-triazol-1-yl)-2-methoxy-4-methylnicotinonitrile

Intermediate 114C and Intermediate 114D was as prepared, by using asimilar synthetic protocol as that of Intermediate 20 and starting fromIntermediate 114A (2.21 g, 12.11 mmol) and Intermediate 28A (1.00 g,10.09 mmol). First eluted compound, designated as Intermediate 114C, wasobtained (0.15 g, 5.45%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.56 (s, 3H), 4.07 (s, 3H), 4.67 (d, J=5.52 Hz, 2H), 5.51(t, J=5.77 Hz, 1H), 7.68 (s, 1H), 8.16 (s, 1H). LCMS (Method-):retention time 0.82 min, [M+1] 246.4. Second eluted compound, designatedas Intermediate 114D, was obtained (0.25 g, 9.60%), as an off whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.55-2.62 (m, 3H), 4.05-4.15 (m,3H), 4.61-4.72 (m, 2H), 5.38 (t, J=5.77 Hz, 1H), 7.83 (s, 1H), 8.76 (s,1H). LCMS (Method-): retention time 0.81 min, [M+1] 246.4.

Intermediate 114

Intermediate 114 was prepared (0.08 g, 36.90%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 114D (0.23 g, 0.89 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.67 (s, 3H), 4.18 (s, 3H), 7.86 (s, 1H), 8.79 (s, 1H),10.21 (s, 1H). LCMS (Method-1): retention time 1.03 min, [M+1] 244.4.

Intermediate 115:6-(4-formyl-2H-1,2,3-triazol-2-yl)-2-methoxy-4-methylnicotinonitrile

Intermediate 115 was prepared (0.38 g, 82.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 114C (0.40 g, 1.63 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.62 (s, 3H), 4.11 (s, 3H), 7.85 (s, 1H), 8.78 (s, 1H),10.21 (s, 1H). LCMS (Method-1): retention time 1.06 min, [M+H] 244.0.

Intermediate 116-I and 116-II:4-methyl-5-(piperidin-3-yl)isobenzofuran-1(3H)-one

Intermediate 116A: 4-methyl-5-(pyridin-3-yl)isobenzofuran-1(3H)-one

Intermediate 116A was prepared (0.42 g, 85.00%), by using a similarsynthetic protocol as that of Intermediate 2C and starting fromIntermediate 2A (0.50 g, 2.20 mmol) and pyridin-3-ylboronic acid (0.27g, 2.20 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 2.29 (s, 3H), 5.45 (s, 2H),7.52 (d, J=7.53 Hz, 1H), 7.56-7.70 (m, 1H), 7.83 (d, J=7.53 Hz, 1H),7.93 (dt, J=7.91, 1.82 Hz, 1H), 8.46-8.76 (m, 2H). LCMS (Method-D):retention time 1.71 min, [M+H] 226.2.

Intermediate 116-I and 116-II

To a solution of Intermediate 116A (0.42 g, 1.87 mmol) in EtOH (50 mL)was added HCl (0.57 mL, 18.65 mmol) and degassed with nitrogen for 5minutes. Platinum(IV)oxide (0.09 g, 0.37 mmol) was added and reactionmixture was stirred under H₂ gas atmosphere at ambient temperature for12 h. The reaction mixture was filtered through Celite® and washed withEtOH (40 mL). The filtrate was evaporated under reduced pressure and theracemate was separated into two individual enantiomers by supercriticalfluid chromatography (SFC) [Chiralpak IC (250×4.6 mm) 5.0 micron; 0.2%DEA in MeOH, Flow: 1.6 mL/min, Temperature: 25° C., UV: 220 nm]. Firsteluted compound (retention time 8.18 min), designated as Intermediate116-I, was obtained (0.12 g, 27.80%) as a brown solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 1.61-2.02 (m, 4H), 2.26-2.47 (m, 3H), 2.69-2.85 (m, 2H),3.02-3.26 (m, 3H), 5.37 (s, 2H), 7.29-7.60 (m, 1H), 7.70 (d, J=8.03 Hz,1H), (1 Exchangeable proton not observed). LCMS (Method-D): retentiontime 0.47 min, [M+H] 232.2. Second eluted compound (retention time 10.32min), designated as Intermediate 116-II, was obtained (0.08 g, 18.55%)as a brown solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62-1.79 (m, 2H),1.81-2.01 (m, 2H), 2.23-2.43 (m, 3H), 2.59-2.84 (m, 2H), 2.95-3.24 (m,3H), 5.36 (s, 2H), 7.49 (d, J=8.03 Hz, 1H), 7.68 (d, J=8.53 Hz, 1H), (1Exchangeable protons not observed). LCMS (Method-D): retention time 0.52min, [M+H] 232.2.

Intermediate 117: 2-(4-formyl-1H-pyrazol-1-yl)isonicotinonitrile

Intermediate 117 was prepared (0.03 g, 22.99%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from1H-pyrazole-4-carbaldehyde (0.05 g, 0.55 mmol) and2-bromoisonicotinonitrile (0.10 g, 0.55 mmol). ¹H NMR (400 MHz, CDCl₃) δppm 7.51 (dd, J=4.88, 1.38 Hz, 1H), 8.09-8.38 (m, 2H), 8.64 (dd, J=5.00,0.75 Hz, 1H), 9.08 (d, J=0.75 Hz, 1H), 10.02 (s, 1H). LCMS (Method-D):retention time 1.42 min, [M+H] 199.0.

Intermediate 118A and 118B:5-(5-hydroxypiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 118C:5-(5-methoxypyridin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 118C was prepared (1.30 g, 24.15%) as a pale yellow solid.by using a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 2A (3.12 g, 13.73 mmol) and(5-methoxypyridin-3-yl)boronic acid (3.00 g, 19.62 mmol). ¹H NMR (400MHz, DMSO-d6) δ ppm 2.23 (s, 3H), 3.89 (s, 3H), 5.47 (s, 2H), 7.38-7.47(m, 1H), 7.53 (d, J=7.53 Hz, 1H), 7.77 (d, J=8.03 Hz, 1H), 8.20 (d,J=1.51 Hz, 1H), 8.37 (d, J=3.01 Hz, 1H). LCMS (Method-D): retention time1.58 min, [M+H] 256.2.

Intermediate 118D:5-(5-hydroxypyridin-3-yl)-4-methylisobenzofuran-1(3H)-one

A solution of Intermediate 118C (1.70 g, 6.66 mmol) in 33% HBr in AcOH(28.2 mL, 166 mmol) was heated at 120° C. for 20 h. The reaction mixturewas cooled to ambient temperature, concentrated to dryness under reducedpressure to obtain Intermediate 118D (1.20 g, 31.40%) as a brown solid.LCMS (Method-1): retention time 0.71 min, [M+H] 242.4. The compound wastaken directly to the subsequent step without further purification orcharacterization.

Intermediate 118A and 118B

A solution of Intermediate 118A (1.20 g, 4.97 mmol) in AcOH (100 mL) wasdegassed with nitrogen for 5 minutes. Platinum(IV)oxide (0.01 mL, 0.50mmol) was added and the reaction mixture was stirred under H₂ gaspressure (50 psi) at ambient temperature for 28 h. The reaction mixturewas filtered through Celite® and washed with MeOH (40 mL). The filtratewas evaporated under reduced pressure. Two diastereomers were separatedby HPLC [Xterra RP 18 (250×4.6 mm) 5 micron; Solvent A: 10 mM Ammoniumbicarbonate, Solvent B: ACN+MeOH (1:1), Gradient: 0-100% B over 18 min,Flow: 1 mL/min, UV: 254 nm]. First eluted compound (retention time 10.33min), designated as Intermediate 118A: Dia-I, was obtained (0.20 g,16.26%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.87-2.02 (m, 2H), 2.18-2.36 (m, 3H), 2.81 (d, J=12.05 Hz, 1H),2.94-3.08 (m, 2H), 3.17 (s, 2H), 3.45-3.58 (m, 1H), 4.69 (br. s., 1H),5.37 (s, 2H), 6.66 (br. s., 1H), 7.45 (d, J=8.03 Hz, 1H), 7.63 (d,J=8.03 Hz, 1H). LCMS (Method-D): retention time 0.49 min, [M+H] 248.1.Second eluted compound (retention time 12.13 min), designated asIntermediate 118B: Dia-II, was obtained (0.07 g, 5.69%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.75 (s, 2H), 1.92 (s, 2H),2.28-2.38 (m., 4H), 2.81 (d, J=12.05 Hz, 1H), 3.17 (s, 1H), 3.61-4.21(m, 2H), 5.37 (br. s., 2H), 6.65 (br. s., 1H), 7.06-7.32 (m, 1H),7.38-7.95 (m, 1H). LCMS (Method-D): retention time 0.50 min, [M+H]248.2.

Intermediate 119A and 119B:5-(5-methoxypiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 119A and 119B was prepared by using a similar syntheticprotocol as that of Intermediate 118A and 118B and starting fromIntermediate 118C (1.27 g, 4.97 mmol). Two diastereomers were separatedby HPLC [Xterra RP 18 (250×4.6 mm) 5 micron; Solvent A: 10 mM Ammoniumbicarbonate, Solvent B: ACN+MeOH (1:1), Gradient: 0-100% B over 18 min,Flow: 1 mL/min, UV: 254 nm]. First eluted compound (retention time 14.48min), designated as Intermediate 119A: Dia-I, was obtained (0.20 g,15.39%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.35-1.85 (m, 5H), 2.16-2.38 (m, 4H), 3.17 (s, 3H), 4.09 (d, J=9.54 Hz,2H), 4.46 (br. s., 1H), 5.39 (d, J=2.93 Hz, 2H), 7.49 (d, J=7.83 Hz,1H), 7.65 (d, J=8.31 Hz, 1H). LCMS (Method-D): retention time 0.78 min,[M+H] 262.2. Second eluted compound (retention time 17.38 min),designated as Intermediate 119B: Dia-I, was obtained (0.20 g, 15.39%) asa brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.85 (m, 5H),2.16-2.38 (m, 4H), 3.17 (s, 3H), 4.09 (d, J=9.54 Hz, 2H), 4.46 (br. s.,1H), 5.39 (d, J=2.93 Hz, 2H), 7.49 (d, J=7.83 Hz, 1H), 7.65 (d, J=8.31Hz, 1H). LCMS (Method-D): retention time 0.77 min, [M+H] 262.2.

Intermediate120:2-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyrimidine-5-carbaldehyde

Intermediate 120 was prepared (0.10 g crude), by using a similarsynthetic protocol as that of Intermediate 20 and starting from2-bromopyrimidine-5-carbaldehyde (0.10 g, 0.54 mmol) and3,5-dimethyl-4H-1,2,4-triazole (0.05 g, 0.54 mmol). LCMS (Method-I):retention time 0.49 min, [M+H] 204.4. The compound was taken directly tothe subsequent step without further purification or characterization.

Intermediate 121:2-(4-formyl-1H-pyrazol-1-yl)-3-methylisonicotinonitrile

Intermediate 121A: 4-cyano-3-methylpyridine 1-oxide

To a solution of 3-methylisonicotinonitrile (5.00 g, 42.30 mmol) in DCM(100 mL) was added 3-chloroperoxybenzoic acid (14.61 g, 85.00 mmol) at0° C. and the resulting reaction mixture was stirred at ambienttemperature for 16 h. The reaction mixture was diluted with water (50mL), basified with 10% NaHCO₃ solution and extracted with ethyl acetate(2×75 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain Intermediate 121A (3.50 g, 61.30%) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.38 (s, 3H), 7.84-7.85 (d,J=6.80 Hz, 1H), 8.21-8.23 (dd, J=1.20 Hz, 6.80 Hz, 1H), 8.41 (s, 1H).LCMS (Method-D): retention time 0.44 min, [M+H] 135.2.

Intermediate 121B:2-(4-formyl-1H-pyrazol-1-yl)-3-methylisonicotinonitrile

A stirring solution of Intermediate 121A (3.5 g, 26.1 mmol) in POCl₃(48.6 mL, 52 mmol) was heated at 100° C. for 3 h. The reaction mixturewas cooled to ambient temperature and poured into cold water (50 mL),basified with 10% NaHCO₃ solution and extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-80g, 0-20% EtOAc/n-Hexane) to obtain Intermediate 121B (0.62 g, 15.57%) asa pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.41-2.83 (m, 3H),7.44 (d, J=5.00 Hz, 1H), 8.39 (dd, J=5.00, 0.75 Hz, 1H). LCMS(Method-D): retention time 1.66 min, [M+H] 153.2.

Intermediate 121

Intermediate 121 was prepared (0.03 g 30.25%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from1H-pyrazole-4-carbaldehyde (0.03 g, 0.33 mmol) and Intermediate 121B(0.05 g, 0.33 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.56-2.69 (m, 3H),7.82-8.07 (m, 1H), 8.12-8.40 (m, 1H), 8.48-8.82 (m, 1H), 8.90-9.29 (m,1H), 9.99 (s, 1H). LCMS (Method-D): retention time 1.43 min, [M+H]213.2.

Intermediate 122-I:5-(5-fluoropiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 122A: ethyl (4-methoxybenzyl)glycinate

To a stirred solution of (4-methoxyphenyl)methanamine (19.05 mL, 146mmol) in DCM (250 mL) was added TEA (20.32 mL, 146 mmol) followed byethyl bromoacetate (16.13 mL, 146 mmol) at 0° C. and the resultingreaction mixture was stirred at ambient temperature for 16 h. Thereaction mixture was diluted with water (250 mL) and extracted with DCM(3×250 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-220g, 35-40% EtOAc/n-hexane)) to obtain Intermediate 122A (21.00 g, 63.90%)as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.22-1.30 (m,3H), 3.39 (s, 2H), 3.74 (s, 2H), 3.80 (s, 3H), 4.19 (q, J=7.03 Hz, 2H),6.68-6.96 (m, 2H), 7.13-7.30 (m, 3H). LCMS (Method-D): retention time1.80 min, [M+H] 224.0.

Intermediate 122B: ethyl N-(4-methoxybenzyl)-N-(2-oxopropyl)glycinate

To a stirred solution of Intermediate 122A (21.00 g, 71.90 mmol) in EtOH(250 mL) was added NaHCO₃ (11.29 g, 134 mmol) followed by1-chloropropan-2-one (11.04 mL, 134 mmol) at 0° C. and the reactionmixture was stirred at ambient temperature for 16 h. The reactionmixture was filtered through Celite® and washed with EtOH (50 mL) andthe filtrate was evaporated under reduced pressure. The residue waspurified by column chromatography (Redisep-220 g, 20% EtOAc/n-hexane) toobtain Intermediate 122B (21.00 g, 80.00%) as a pale yellow liquid. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.26 (t, J=7.25 Hz, 3H), 2.12 (s, 3H), 3.44(s, 2H), 3.49 (s, 2H), 3.77 (s, 2H), 3.80 (s, 3H), 4.16 (q, J=7.09 Hz,2H), 6.70-6.98 (m, 2H), 7.26 (s, 2H). LCMS (Method-D): retention time2.19 min, [M+H] 280.2.

Intermediate 122C:1-(4-methoxybenzyl)-5-oxo-1,2,5,6-tetrahydropyridin-3-yltrifluoromethanesulfonate

To a stirring solution of Intermediate 122B (16.30 g, 58.40 mmol) in THE(50 mL) was added 1M potassium tert-butoxide in THE (58.4 mL, 58.4 mmol)followed by 2-[n,n-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine(22.91 g, 58.4 mmol) at 0° C. and the resulting reaction mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasdiluted with NH₄Cl solution (50 mL) and extracted with diethyl ether(2×75 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-80g, 12-15% EtOAc/n-hexane) to obtain Intermediate 122C (4.40 g, 20.64%)as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.25 (s, 2H),3.47 (s, 2H), 3.67 (s, 2H), 3.71-4.02 (m, 3H), 6.15 (t, J=1.25 Hz, 1H),6.74-6.96 (m, 2H), 7.12-7.24 (m, 2H). LCMS (Method-D): retention time2.81 min, [M+H] 366.2.

Intermediate 122_(D):1-(4-methoxybenzyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-1,6-dihydropyridin-3(2H)-one

To a solution of Intermediate 122C (4.20 g, 11.50 mmol) in dioxane (100mL) was added Intermediate 2B (3.15 g, 11.50 mmol) followed by potassiumphosphate tribasic (4.88 g, 22.99 mmol) and the resulting mixture wasdegassed with argon for 15 minutes. PdCl₂(dppf)₂CH₂Cl₂ (0.47 g, 0.58mmol) was added and the resulting reaction mixture was stirred at 40° C.for 12 h. The reaction mixture was cooled to ambient temperature,filtered through Celite® and washed with ethyl acetate (50 mL). Thefiltrate was evaporated under reduced pressure and the residue waspurified by column chromatography (Redisep-40 g, 70% EtOAc/n-hexane) toobtain Intermediate 122D (3.20 g, 72.80%). ¹H NMR (400 MHz, CDCl₃) δ ppm2.22 (s, 3H), 3.31 (s, 2H), 3.37 (s, 2H), 3.68 (s, 2H), 3.78-3.83 (m,3H), 5.08-5.34 (m, 2H), 6.07 (t, J=1.76 Hz, 1H), 6.84-6.89 (m, 2H),7.22-7.24 (m, 1H), 7.25-7.29 (m, 2H), 7.76 (d, J=8.03 Hz, 1H). LCMS(Method-D): retention time 2.39 min, [M+H] 364.2.

Intermediate 122E and 122F:5-(5-hydroxy-1-(4-methoxybenzyl)piperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

To a solution of Intermediate 122_(D) (2.00 g, 5.50 mmol) in MeOH (50mL) was added nickel(II) chloride hexahydrate (2.62 g, 11.01 mmol)followed by NaBH₄ (0.416 g, 11.01 mmol) and the resulting reactionmixture was stirred at 50° C. for 2 h. The reaction mixture was cooledto ambient temperature, concentrated to dryness under reduced pressure,diluted with 10% NH₄Cl solution (50 mL) and extracted with 10% MeOH inCHCl₃ (2×50 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous sodium sulfate and evaporated under reducedpressure. The diastereomeric mixture was separated by columnchromatography (Redisep—40 g, 10% MeOH/CHCl₃). First eluted compound,designated as Intermediate 122E: Dia-I, was obtained (0.70 g, 34.60%) asa pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.80 (m, 4H),2.06-2.27 (m, 4H), 3.39-3.60 (m, 4H), 3.63-3.78 (s, 3H), 3.82 (br. s.,1H), 4.60 (d, J=5.02 Hz, 1H), 5.13-5.43 (m, 2H), 6.88 (d, J=9.04 Hz,2H), 7.13-7.36 (m, 2H), 7.62 (s, 2H). LCMS (Method-J): retention time1.14 min, [M+H] 368.1. Second eluted compound, designated asIntermediate 122F: Dia-I, was obtained (0.90 g, 44.50%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (q, J=12.05 Hz, 1H),1.70-1.97 (m, 3H), 2.21 (s, 3H), 2.63-2.82 (m, 1H), 2.98 (d, J=5.52 Hz,1H), 3.04-3.21 (m, 1H), 3.38-3.56 (m, 3H), 3.60-3.81 (m, 3H), 4.82 (d,J=5.02 Hz, 1H), 5.36 (s, 2H), 6.73-6.95 (m, 2H), 7.21 (d, J=9.04 Hz,2H), 7.45 (d, J=8.03 Hz, 1H), 7.63 (d, J=8.03 Hz, 1H). LCMS (Method-D):retention time 0.93 min, [M+H] 368.1.

Intermediate 122G-I and 122G-II:5-(5-fluoro-1-(4-methoxybenzyl)piperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 122G-I and 122G-II was prepared by using a similarsynthetic protocol as that of Intermediate 4B and starting fromIntermediate 122E (0.03 g, 0.33 mmol) and DAST (0.43 mL, 3.27 mmol). Theracemate was separated into two individual enantiomers by SFC [ChiralpakAD-H (250×4.6 mm) 5.0 micron; 0.2% NH₄OH in ACN+MaOH (1:1), Flow: 70.0g/min, Temperature: 30° C., UV 230 nm]. First eluted compound (retentiontime 5.0 min), designated as Intermediate 122G-I, was obtained (0.120 g,20.00%) as a pale yellow solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.57 (s,1H), 1.72 (t, J=12.22 Hz, 1H), 2.00 (t, J=11.06 Hz, 1H), 2.12 (td,J=9.91, 5.28 Hz, 1H), 2.24 (s, 2H), 2.26-2.32 (m, 1H), 2.36 (s, 1H),2.82 (d, J=11.23 Hz, 1H), 3.12-3.36 (m, 1H), 3.50-3.63 (m, 2H), 3.80 (s,3H), 4.65-4.89 (m, 1H), 5.23 (s, 2H), 6.81-6.89 (m, 2H), 7.15-7.24 (m,2H), 7.41 (d, J=7.93 Hz, 1H), 7.73 (d, J=7.93 Hz, 1H). ¹⁹F NMR (300 MHz,CDCl₃) δ ppm −180.45. LCMS (Method-D): retention time 3.09 min, [M+H]370.2. Second eluted compound (retention time 7.0 min), designated asIntermediate 122G-II, was obtained (0.110 g, 18.23%) as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.55 (br. s., 1H), 1.61-1.81 (m,1H), 2.00 (t, J=11.29 Hz, 1H), 2.06-2.17 (m, 1H), 2.24 (s, 2H), 2.27(br. s., 1H), 2.35 (s, 1H), 2.82 (d, J=11.04 Hz, 1H), 3.18 (br. s., 1H),3.32 (br.s., 1H, 3.46-3.65 (m, 2H), 3.80 (s, 2H), 4.58-4.92 (m, 1H),5.15-5.28 (m, 2H), 6.73-6.94 (m, 2H), 7.11-7.24 (m, 2H), 7.41 (d, J=8.03Hz, 1H), 7.73 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 2.91min, [M+H] 370.5. ¹⁹F NMR (400 MHz, CDCl₃) δ ppm −180.46.

Intermediate 122-I

A solution of Intermediate 122G-I (0.12 g, 0.33 mmol) in AcOH (10 mL)was purged with nitrogen for 5 minutes. To the resulting reactionmixture, 20% Pd(OH)₂/C (0.01 g, 0.06 mmol) was added and stirred atambient temperature for 12 h under H₂ atmosphere. The reaction mixturewas filtered through Celite®, washed with EtOH (10 mL) and the filtratewas concentrated under reduced pressure, diluted with aq. NaHCO₃ (20 mL)and extracted with ethyl acetate (2×30 mL). The combined organic layerswere washed with brine (10 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 122-I (0.08 g,95.00%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (br. s.,1H), 2.29 (s, 3H), 2.31 (s, 1H), 2.34 (br. s., 1H), 2.37 (s, 1H), 2.43(s, 1H), 2.82 (d, J=12.55 Hz, 1H), 3.10 (t, J=10.79 Hz, 1H), 3.24 (d,J=12.55 Hz, 2H), 4.48-4.77 (m, 1H), 5.39 (s, 2H), 7.54 (d, J=8.53 Hz,1H), 7.66 (d, J=8.03 Hz, 1H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ ppm −175.06.LCMS (Method-D): retention time 1.32 min, [M+H] 250.2.

Intermediate 123-I, II, III and IV:5-(6-(1-hydroxyethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 123A:5-(6-(hydroxymethyl)pyrazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 123A was prepared (6.00 g, 87.00%), by using a similarsynthetic protocol as that of Intermediate 2C and starting fromIntermediate 2B (7.02 g, 25.60 mmol) and (6-chloropyrazin-2-yl)methanol(3.70 g, 25.60 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.98-1.23 (m, 2H),2.24-2.36 (m, 3H), 5.49 (s, 2H), 7.42-7.60 (m, 1H), 7.70 (d, J=7.53 Hz,1H), 7.81 (d, J=8.03 Hz, 1H), 8.77 (d, J=6.53 Hz, 2H). LCMS (Method-D):retention time 0.92 min, [M+H] 257.0.

Intermediate 123B:6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrazine-2-carbaldehyde

Intermediate 123B was prepared (4.40 g, 55.40%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 123A (8.00 g, 31.20 mmol) and Dess-Martin periodinane(26.50 g, 62.40 mmol). ¹H (400 MHz, CDCl₃) δ ppm 2.42 (s, 3H), 5.37 (s,2H), 7.69 (d, J=7.75 Hz, 1H), 7.94 (d, J=7.75 Hz, 1H), 8.99 (s, 1H),9.21 (s, 1H), 10.12-10.29 (m, 1H). LCMS (Method-D): retention time 1.18min, [M+H] 255.0.

Intermediate 123C:5-(6-(1-hydroxyethyl)pyrazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 123C was prepared (0.95 g, 89.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 72A andstarting from Intermediate 123B (1.00 g, 3.93 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.47 (d, J=6.53 Hz, 3H), 2.22-2.39 (m, 3H), 4.90 (dd,J=6.53, 4.52 Hz, 1H), 5.51 (s, 2H), 5.69 (d, J=4.80 Hz, 1H), 7.73 (d,J=8.03 Hz, 1H), 7.83 (d, J=8.03 Hz, 1H), 8.82 (s, 2H). LCMS (Method-1):retention time 0.78 min, [M+H] 271.2.

Intermediate 123-I, II, III and IV

Intermediate 123-I was prepared by using a similar synthetic protocol asthat of Intermediate 2-I and 2-II and starting from Intermediate 123C(0.90 g, 3.33 mmol). The racemate was separated into four individualenantiomers by SFC [Chiralpak IC (250×4.6 mm) 5.0 micron; 0.2% NH₄OH inACN+MeOH (1:1), Flow: 4.0 mL/min, Temperature: 30° C., UV: 235 nm].First eluted compound (retention time 12.40 min), designated asIntermediate 123-I, was obtained (0.08 g, 8.69%) as a pale yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.11 (m, 3H), 1.56-1.76 (m, 2H),2.15-2.27 (m, 3H), 2.29-2.36 (m, 3H), 2.82 (d, J=11.74 Hz, 2H), 3.17 (s,1H), 4.00 (dd, J=9.78, 2.45 Hz, 1H), 4.66 (br. s., 1H), 5.28-5.44 (m,2H), 7.67 (d, J=8.07 Hz, 1H), 7.75-7.89 (m, 1H). LCMS (Method-D):retention time 0.51 min, [M+H] 277.2. Second eluted compound (retentiontime 12.80 min), designated as Intermediate 123-II, was obtained (0.03g, 3.26%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 0.98-1.17(m, 3H), 1.33 (dt, J=13.76, 7.18 Hz, 1H), 2.05 (s, 1H), 2.12-2.25 (m,2H), 2.25-2.37 (m, 4H), 2.75-2.92 (m, 2H), 3.82-4.13 (m, 2H), 4.51-4.72(m, 1H), 5.39 (s, 2H), 7.56-7.72 (m, 1H), 7.82 (dd, J=7.95, 4.03 Hz,1H). LCMS (Method-D): retention time 0.51 min, [M+H]277.2. Third elutedcompound (retention time 15.0 min), designated as Intermediate 123-III,was obtained (0.18 g, 19.56%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.96-1.15 (m, 3H), 2.10-2.37 (m, 4H), 2.59-2.72 (m, 1H),2.84 (d, J=13.05 Hz, 1H), 2.96 (d, J=11.04 Hz, 1H), 3.18 (s, 3H),3.45-3.61 (m, 1H), 4.04 (dd, J=9.79, 2.76 Hz, 1H), 4.46 (br. s., 1H),5.19-5.49 (m, 2H), 7.67 (d, J=8.03 Hz, 1H), 7.74-7.89 (m, 1H). LCMS(Method-D): retention time 0.59 min, [M+H] 277.2. Fourth eluted compound(retention time 17.47 min), designated as Intermediate 123-IV, wasobtained (0.15 g, 16.30%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.09 (d, J=6.02 Hz, 3H), 2.21 (d, J=11.55 Hz, 1H),2.26-2.34 (m, 3H), 2.57-2.70 (m, 1H), 2.83 (d, J=12.05 Hz, 1H), 2.95 (d,J=10.04 Hz, 1H), 3.17 (s, 3H), 3.51 (d, J=4.52 Hz, 1H), 3.91-4.18 (m,1H), 4.46 (d, J=4.02 Hz, 1H), 5.27-5.48 (m, 2H), 7.66 (d, J=8.03 Hz,1H), 7.81 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 0.59 min,[M+H]277.2.

Intermediate124:5-(6-(difluoromethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 124A:5-(6-(difluoromethyl)pyrazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 124A was prepared (0.07 g, 64.40%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 4B andstarting from Intermediate 123B (0.10 g, 0.39 mmol) and DAST (0.10 mL,0.78 mmol). ¹H (400 MHz, CDCl₃) δ ppm 2.39 (s, 3H), 5.35 (s, 2H),6.46-6.98 (m, 1H), 7.65 (d, J=7.53 Hz, 1H), 7.91 (d, J=8.03 Hz, 1H),8.79-9.07 (m, 2H). LCMS (Method-D): retention time 2.16 min, [M+H]277.2.

Intermediate 124

Intermediate 124 was prepared (0.30 g, crude) as a pale yellow solid, byusing a similar synthetic protocol as that of Intermediate 2-I and 2-IIand starting from Intermediate 124A (0.28 g, 1.01 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.94-1.05 (m, 1H), 1.84-1.95 (m, 3H), 2.15-2.40 (m,2H), 2.74-3.00 (m, 2H), 3.06-3.22 (m, 2H), 4.00-4.22 (m, 1H), 5.27-5.43(m, 2H), 5.67-6.02 (m, 1H), 7.57-7.73 (m, 1H), 7.80 (dd, J=8.03, 4.02Hz, 1H). LCMS (Method-I): retention time 0.87 min, [M+H]283.2.

Intermediate 125:1-(5-methylpyrazin-2-yl)-1H-pyrazole-4-carbaldehyde

To a solution of 2-chloro-5-methylpyrazine (2.00 g, 15.56 mmol) in DMF(50 mL) was added 1H-pyrazole-4-carbaldehyde (2.24 g, 23.34 mmol)followed by Cs₂CO₃ (10.14 g, 31.10 mmol) and the resulting reactionmixture was heated at 100° C. for 6 h. The reaction mixture was cooledto ambient temperature, concentrated to dryness under reduced pressure,diluted with water (50 mL) and extracted with ethyl acetate (2×75 mL).The combined organic layers was washed with brine (30 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep—80 g, 0-100%EtOAc/n-hexane) to obtain Intermediate 125 (1.10 g, 37.10%) as a paleyellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.58 (s, 3H), 8.36 (s,1H), 8.54 (s, 1H), 9.14 (s, 1H), 9.31 (s, 1H), 9.98 (s, 1H). LCMS(Method-D): retention time 1.25 min, [M+H] 189.2.

Intermediate 126:1-(6-methoxypyrimidin-4-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 126 was prepared (1.50 g, 53.10%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 4-chloro-6-methoxypyrimidine (2.00 g, 13.84 mmol) and1H-pyrazole-4-carbaldehyde (1.99 g, 20.75 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.03 (s, 3H), 7.30 (d, J=1.00 Hz, 1H), 8.38 (s, 1H), 8.84(s, 1H), 9.37 (s, 1H), 9.99 (s, 1H). LCMS (Method-D): retention time1.60 min, [M+H] 205.2.

Intermediate 127: 1-(2-methoxypyrimidin-5-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 127 was prepared (0.20 g, 18.51%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from 1H-pyrazole-4-carbaldehyde (0.76 g, 7.94 mmol) and5-bromo-2-methoxypyrimidine (1.00 g, 5.29 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.99 (s, 3H), 8.36 (s, 1H), 9.14 (s, 2H), 9.22 (s, 1H),9.94 (s, 1H). LCMS (Method-D): retention time 1.0 min, [M+H] 205.2.

Intermediate 128: 1-(2-methylpyrimidin-5-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 128 was prepared (0.02 g, 18.39%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from 1H-pyrazole-4-carbaldehyde (0.08 g, 0.87 mmol) and5-bromo-2-methylpyrimidine (0.10 g, 0.58 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.62-2.89 (m, 3H), 8.39 (s, 1H), 9.25 (s, 2H), 9.34 (s,1H), 9.95 (s, 1H). LCMS (Method-D): retention time 0.71 min, [M+H]189.2.

Intermediate 129:6-(3-formylisoxazol-5-yl)-4-methylnicotinonitrile

Intermediate 129A: ethyl 5-(tributylstannyl)isoxazole-3-carboxylate

To a solution of ethyl 2-chloro-2-(hydroxyimino)acetate (0.72 g, 4.76mmol) in diethyl ether (15 mL) was added tributylstannylacetylene (0.92mL, 3.17 mmol) followed by TEA (0.88 mL, 6.35 mmol) and the resultingreaction mixture was stirred at ambient temperature for 16 h. Thereaction mixture was filtered through Celite® and washed with diethylether (50 mL). The filtrate was evaporated under reduced pressure toobtain Intermediate 129A (0.60 g, 43.90%) as a pale yellow liquid. ¹HNMR (300 MHz, CDCl₃) δ ppm 0.76-0.95 (m, 12H), 1.02-1.11 (m, 2H),1.13-1.24 (m, 3H), 1.24-1.35 (m, 5H), 1.37-1.47 (m, 4H), 1.48-1.72 (m,4H), 4.27-4.58 (m, 2H), 6.80 (s, 1H). LCMS (Method-D): retention time2.76 min, [M+H] 432.2.

Intermediate 129B: ethyl5-(5-cyano-4-methylpyridin-2-yl)isoxazole-3-carboxylate

A stirring solution of Intermediate 129A (0.06 g, 1.27 mmol) and6-bromo-4-methylnicotinonitrile (0.25 g, 1.27 mmol) in dioxane (10 mL)was degassed with nitrogen for 20 minutes. To the stirring solution wasaddedbis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.09 g, 0.13 mmol) and was degassed again for 10 minutes. The resultingreaction mixture was heated at 110° C. for 16 h then cooled to ambienttemperature and filtered through Celite®. The filtrate obtained, wasconcentrated under reduced pressure. The residue was purified by columnchromatography (Redisep-24 g, 12-14% EtOAc/n-Hexane) to obtainIntermediate 129B (0.07 g, 21.45%) as a pale yellow solid. ¹H NMR (400MHz, CDCl₃) δ ppm 1.39-1.52 (m, 3H), 2.55-2.81 (m, 3H), 4.35-4.67 (m,2H), 7.42 (s, 1H), 7.95 (s, 1H), 8.72-8.96 (m, 1H). LCMS (Method-H):retention time 2.71 min, [M+1] 258.2.

Intermediate 129C:6-(3-(hydroxymethyl)isoxazol-5-yl)-4-methylnicotinonitrile

Intermediate 129C was prepared (0.01 g, 71.70%), by using a similarsynthetic protocol as that of Intermediate 60B and starting fromIntermediate 129B (0.02 g, 0.58 mmol) and NaBH₄ (0.09 mg, 2.33 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.55-2.64 (m, 3H), 4.60 (br. s., 2H), 5.61(d, J=4.02 Hz, 1H), 7.40-7.66 (m, 1H), 8.14 (s, 1H), 8.96-9.10 (m, 1H).LCMS (Method-D): retention time 2.79 min, [M+H] 216.2.

Intermediate 129

Intermediate 129 was prepared (0.08 g, 55.00%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 129C (0.01 g, 0.46 mmol) and Dess-Martin periodinane (26.5g, 62.40 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.01-2.20 (m, 3H), 7.39(s, 1H), 7.96 (s, 1H), 8.89 (s, 1H), 10.25 (s, 1H). LCMS (Method-D):retention time 0.75 min, [M+H] 214.0.

Intermediate 130-I:5-((2R,6S)-4-((1H-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzo-furan-1(3H)-one

Intermediate 130A: tert-butyl 4-formyl-1H-imidazole-1-carboxylate

To a stirring solution of 1H-imidazole-4-carbaldehyde (2.00 g, 20.81mmol) in THE (20 mL) was added DMAP (0.64 g, 5.20 mmol) and TEA (5.80ml, 41.60 mmol) followed by Boc-anhydride (5.80 mL, 24.98 mmol) and theresulting reaction mixture was stirred as ambient temperature for 18 h.The reaction mixture was concentrated to dryness under reduced pressureand diluted with water (50 mL). The solid precipitate was filtered anddried under vacuum to obtain Intermediate 130A (2.50 g, 49.00%) as apale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59 (s, 9H),8.37-8.39 (d, J=5.40 Hz, 2H), 9.80 (s., 1H). LCMS (Method-O): retentiontime 1.00 min, [M−56] 141.2.

Intermediate 130B-I: tert-butyl4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-imidazole-1-carboxylate

Intermediate 130B-I was prepared (0.8 g, 22.39%), by using a similarsynthetic protocol as that of Intermediate 4 and starting fromIntermediate 51-I (1.30 g, 5.28 mmol) and Intermediate 130A (1.24 g,6.33 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 0.60-0.62 (d, J=6.00 Hz, 3H),1.59 (s, 9H), 1.37-1.43 (m, 2H), 2.29-2.31 (m, 2H), 2.66 (s, 3H), 2.94(s, 2H), 3.69-3.71 (m, 1H), 4.71 (s, 2H), 6.8 (s, 1H), 7.05-7.07 (m,1H), 7.12-7.14 (m, 1H), 7.25 (s, 1H), 7.51 (s, 1H), (1 Exchangeableproton not observed). LCMS (Method-O): retention time 1.17 min, [M+1]427.3.

Intermediate 130-I

Intermediate 130-I was prepared (0.65 g, 99.90%), by using a similarsynthetic protocol as that of Intermediate 38-I and starting fromIntermediate 130B-I (0.70 g, 1.64 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.40 (d, J=6.60 Hz, 3H), 2.39 (s, 3H), 2.82 (m, 2H), 2.98 (m, 1H), 3.48(s, 2H), 3.97 (s, 2H), 4.9 (br. s., 1H), 5.40-5.53 (m, 2H), 7.75 (s,1H), 7.81 (d, J=7.80 Hz, 1H), 8.23 (d, J=8.10 Hz, 1H), 9.1 (s, 1H),10.20 (b.s, 2H). LCMS (Method-O): retention time 0.51 min, [M+H] 327.4.

Intermediate 13I-I:(R)-6-(4-(((2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)amino)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 131A-I:(R)-2-(2-amino-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)isoindoline-1,3-dione

Intermediate 131A-I was prepared (0.15 g, 97.00%), by using a similarsynthetic protocol as that of Intermediate 19-I and starting fromIntermediate 18C-I (0.20 g, 0.458 mmol) and TFA (2 mL, 26.0 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.33-2.37 (m, 3H), 3.16 (dd, J=13.05, 5.02Hz, 1H), 3.66 (dd, J=13.05, 9.54 Hz, 1H), 5.35-5.41 (m, 2H), 5.50 (dd,J=9.79, 5.27 Hz, 1H), 7.70 (s, 1H), 7.76-7.81 (m, 1H), 7.82-7.89 (m,4H). (2 Exchangeable protons not observed). LCMS (Method-1): retentiontime 0.81 min, [M+H] 337.3.

Intermediate 131B-I:(R)-6-(4-(((2-(1,3-dioxoisoindolin-2-yl)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)amino)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 131B-I was prepared (1.1 g, 45.60%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 4 andstarting from Intermediate 131A-I (1.7 g, 3.03 mmol) and6-(4-formyl-H-pyrazol-1-yl)-4-methylnicotinonitrile (0.98 g, 3.03 mmol).¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27-2.36 (m, 3H), 2.57 (s, 3H), 3.13(dd, J=12.30, 5.27 Hz, 1H), 3.63-3.75 (m, 3H), 5.37 (d, J=3.01 Hz, 2H),5.67 (dd, J=10.04, 5.02 Hz, 1H), 7.68 (d, J=8.03 Hz, 1H), 7.75 (s, 1H),7.81 (d, J=8.03 Hz, 1H), 7.84 (s, 4H), 7.94 (s, 1H), 8.43 (s, 1H), 8.80(s, 1H). (1 Exchangeable proton not observed). LCMS (Method-I):retention time 1.46 min, [M+H] 533.5.

Intermediate 131-I

Intermediate 131-I was prepared (0.03 g, 51.00%), by using a similarsynthetic protocol as that of Intermediate 18-I and starting fromIntermediate 131B-I (0.13 g, 0.12 mmol) and hydrazine hydrate (0.06 mL,1.22 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ 2.15-2.29 (m, 5H), 2.32-2.38 (m,1H), 2.57 (s, 3H), 2.60-2.70 (m, 1H), 3.17 (s, 1H), 3.59-3.76 (m, 2H),4.31 (dd, J=8.56, 4.16 Hz, 1H), 5.35 (s, 2H), 7.63 (d, J=8.07 Hz, 1H),7.76 (d, J=8.07 Hz, 1H), 7.84 (s, 1H), 7.97 (s, 1H), 8.50 (s, 1H), 8.83(s, 1H). LCMS/HPLC (Method-R): retention time 0.98 min, [M+H] 403.1,purity: 98.53%. (Method-S): retention time 1.28 min, [M+H] 403.1,purity: 98.81%. Chiral purity (Method-XVII): retention time 5.86 min,100% ee.

Intermediate 132-I:(R)-5-(4-((5-bromopyrimidin-2-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 132A: 5-bromo-2-(bromomethyl)pyrimidine

To a stirred solution of 5-bromo-2-methylpyrimidine (5.00 g, 28.90 mmol)in CCl₄ (40 mL) was added AIBN (0.48 g, 2.89 mmol) andN-bromosuccinimide (5.14 g, 28.9 mmol) and the reaction mixture washeated at 80° C. for 48 h. The reaction mixture was cooled to ambienttemperature. The solid precipitate was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (Redisep-80 g, 0-15% EtOAc/n-hexane) to obtainIntermediate 132A (1.05 g, 12.98%) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.68 (s, 2H), 9.03 (s, 2H). LCMS (Method-I):retention time 1.03 min, [M+1] 252.9.

Intermediate 132-I

To a stirring solution of Intermediate 123A (0.38 g, 1.63 mmol) andIntermediate 2-I (0.41 g, 1.63 mmol) in THE (20 mL) was added DIPEA(0.69 mL, 3.97 mmol) and the reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was diluted with water (40mL) and extracted with ethyl acetate (3×40 mL). The combined organiclayers were washed with brine (30 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography (Redisep-24 g, 2-4% MeOH/CHCl₃) to obtainIntermediate 132-I (0.32 g, 28.40%) as a brown solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.89-2.06 (m, 1H), 2.20-2.36 (m, 4H), 2.74-3.01 (m, 4H),3.74 (s, 2H), 4.01-4.13 (m, 1H), 5.38 (s, 2H), 7.64 (d, J=8.07 Hz, 1H),7.78 (d, J=8.07 Hz, 1H), 8.96 (s, 2H), (1 Exchangeable proton notobserved). LCMS (Method-D): retention time 1.17 min, [M+H] 405.0.

Intermediate133:6-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methoxy-2-methylnicotinonitrile

Intermediate 133A: bis(2,4,6-trichlorophenyl) malonate

A mixture of malonic acid (20.00 g, 192.00 mmol), 2,4,6-trichlorophenol(76.00 g, 384.00 mmol) and POCl₃ (50 mL) was refluxed for 12 h. Thereaction mixture was cooled to 70° C. and poured into ice water. Thesolid precipitate was collected by filtration, washed with water anddried under vacuum to obtain Intermediate 133A (70.30 g, 67.20%) as apale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.91-4.17 (m, 2H),7.33-7.59 (m, 4H). LCMS: The compound did not ionize well.

Intermediate 133B:4-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile

A mixture of 3-aminoacrylonitrile (10.25 g, 151.00 mmol) andIntermediate 133A (70.30 g, 152.00 mmol) in diglyme (75 mL) was heatedat 120° C. for 2.5 h. The mixture was cooled to ambient temperature andpoured into Et₂O (40 mL) and filtered. The precipitate was washed withEt₂O (15 mL) to obtain Intermediate 133B (13.50 g, 59.70%) as a darkbrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25-2.41 (m, 3H), 5.49 (s,1H), 11.85 (br. s., 2H). LCMS (Method-1): retention time 0.32 min, [M+1]151.3.

Intermediate 133C: 4,6-dichloro-2-methylnicotinonitrile

A stirring solution of Intermediate 133B (10.70 g, 71.30 mmol) in POCl₃(6.64 ml, 71.3 mmol) was heated at 100° C. for 16 h. The reactionmixture was concentrated under reduced pressure, diluted water (200 mL),basified with solid Na₂CO₃ and extracted with ethyl acetate (3×200 mL).The combined organic layers were washed with brine (100 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-120 g, 0-5%EtOAc/n-Hexane) to obtain Intermediate 133C (8.50 g, 57.40%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.69 (s, 3H), 8.02 (s,1H). LCMS: (Method-1): retention time 1.16 min, [M+1] 188.3.

Intermediate 133D: 6-chloro-4-methoxy-2-methylnicotinonitrile andIntermediate 133E: 4-chloro-6-methoxy-2-methylnicotinonitrile

Intermediate 133D and Intermediate 133E was as prepared, by using asimilar synthetic protocol as that of Intermediate 114A and startingfrom Intermediate 133C (8.50 g, 45.40 mmol). First eluted compound,designated as Intermediate 133D, was obtained (5.50 g, 66.30%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.57 (s, 3H), 4.02 (s,3H), 7.35 (s, 1H). LCMS (Method-I): retention time 0.99 min, [M+1]183.3.Second eluted compound, designated as Intermediate 133E, was obtained(1.50 g, 18.07%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.62 (s, 3H) 3.94 (s, 3H) 7.17 (s, 1H). LCMS (Method-I): retention time1.24 min, [M+1] 183.3.

Intermediate 133F:6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methoxy-2-methylnicotinonitrileand Intermediate and 133G:6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-4-methoxy-2-methylnicotinonitrile

Intermediate 133F and Intermediate 133G was as prepared, by using asimilar synthetic protocol as that of Intermediate 20 and starting fromIntermediate 133D (1.84 g, 10.09 mmol) and Intermediate 28A (1.00 g,10.09 mmol). First eluted compound, designated as Intermediate 133F, wasobtained (0.37 g, 10.00%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.65 (s, 3H), 4.11 (s, 3H), 4.68 (d, J=5.02 Hz, 2H), 5.55(t, J=5.77 Hz, 1H), 7.56 (s, 1H), 8.17 (s, 1H). LCMS (Method-I):retention time 0.75 min, [M+1] 246.1. Second eluted compound, designatedas Intermediate 133G, was obtained (0.27 g, 9.33%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.67 (s, 3H), 4.14 (s, 3H), 4.64(d, J=4.02 Hz, 2H), 5.27-5.42 (m, 1H), 7.74 (s, 1H), 8.68 (s, 1H). LCMS(Method-1): retention time 0.80 min, [M+1] 246.1.

Intermediate 133

Intermediate 133 was prepared (0.35 g, 94.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 133F (0.38 g, 1.53 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.70 (s, 3H), 4.15 (s, 3H), 7.73 (s, 1H), 8.79 (s, 1H),10.22 (s, 1H). LCMS (Method-1): retention time 0.92 min, [M+H] 244.1.

Intermediate 134:6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-methoxy-2-methylnicotinonitrile

Intermediate 134 was prepared (0.26 g, 95.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 133G (0.28 g, 1.12 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.70 (s, 3H), 4.17 (s, 3H), 7.84 (s, 1H), 9.56 (s, 1H),10.14 (s, 1H). LCMS (Method-1): retention time 1.00 min, [M−H] 242.1.

Intermediate 135:1-(4-methoxy-1,3,5-triazin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 135 was prepared (0.70 g, 32.80%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 1H-pyrazole-4-carbaldehyde (1.00 g, 10.41 mmol) and2-chloro-4-methoxy-1,3,5-triazine (1.52 g, 10.41 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.11 (s, 3H), 8.39 (s, 1H), 8.60 (s, 1H), 9.47 (s, 1H),10.01 (s, 1H). LCMS (Method-1): retention time 0.62 min, [M+H] 206.2.

Intermediate 136-I:5-((2R,6R)-6-(hydroxymethyl)-1-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 136A-I: tert-butyl(3R,5R)-3-(hydroxymethyl)-4-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a stirred solution of Intermediate 38D-I (0.15 g, 0.41 mmol) andparaformaldehyde (0.05 g, 1.63 mmol) in MeOH (15 mL) was added sodiumcyanoborohydride (0.51 g, 8.16 mmol) and the resultant mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasdiluted with water (30 mL) and extracted with DCM (3×30 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-24 g, 0-2%MeOH/CHCl₃) to obtain Intermediate 136A-I (0.15 g, 96.00%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (d, J=2.20 Hz,9H), 1.98 (d, J=2.20 Hz, 3H), 2.20 (br. s., 1H), 2.33 (br. s., 3H),2.61-2.80 (m, 3H), 3.17 (dd, J=5.26, 3.06 Hz, 1H), 3.46 (d, J=10.52 Hz,2H), 3.73 (br. s., 2H), 4.11 (d, J=5.38 Hz, 1H), 4.71 (br. s., 1H), 5.43(br. s., 1H), 7.72 (br. s., 1H). LCMS (Method-1): retention time 1.06min, [M+H] 377.3.

Intermediate 136-I

Intermediate 136-I was prepared (0.10 g, 91.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 38-I andstarting from Intermediate 136A-I (1.00 g, 10.41 mmol) and 4M HCl indioxane (5 mL, 20.00 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98 (s,3H), 2.33 (s, 3H), 2.55 (br. s., 1H), 2.77 (t, J=11.86 Hz, 1H), 2.90 (t,J=11.98 Hz, 1H), 3.07-3.21 (m, 2H), 3.36-3.53 (m, 2H), 3.63-3.75 (m,1H), 3.91 (d, J=10.27 Hz, 1H), 4.85 (t, J=5.14 Hz, 1H), 5.31-5.48 (m,2H), 7.73 (s, 2H). LCMS (Method-1): retention time 0.46 min, [M+H]277.2.

Intermediate 137:1-(5-formylpyrimidin-2-yl)-1H-imidazole-4-carbonitrile

Intermediate 137 was prepared (0.40 g, 37.50%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 2-chloropyrimidine-5-carbaldehyde (1.00 g, 5.38 mmol) and1H-imidazole-4-carbonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ ppm, 8.90 (s,2H), 9.26 (s, 1H), 10.11 (s, 1H), 10.14 (s, 1H). LCMS (Method-H):retention time 0.91 min, [M+1] 200.05.

Intermediate 138:2-(4-methyl-1H-imidazol-1-yl)pyrimidine-5-carbaldehyde

To a stirring solution of 2-chloropyrimidine-5-carbaldehyde (3.00 g,21.05 mmol) in DMSO (20 mL) was added K₂CO₃ (7.27 g, 52.60 mmol)followed by 4-methyl-1H-imidazole (2.59 g, 31.6 mmol) and the resultingmixture was stirred at ambient temperature for 30 minutes. The reactionmixture was poured into ice cold water (50 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography(Redisep-24 g, 80% EtOAc/n-hexane) to obtain Intermediate 138 (1.40 g,34.30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H),7.72 (t, J 1.2 Hz 1H), 8.56 (d, J 1.2 Hz, 1H), 9.26 (s, 2H) 10.09 (s,1H). LCMS (Method-D): retention time 1.07 min, [M+H] 189.1.

Intermediate139:1-(5-formylpyrimidin-2-yl)-3-methyl-1H-pyrazole-4-carbonitrile

Intermediate 139 was prepared (0.30 g, 40.10%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) and4-methyl-H-pyrazole-3-carbonitrile (0.41 g, 3.86 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.30 (d, J 1.00 Hz, 3H), 8.65 (s, 1H), 8.90 (s, 1H), 9.36(s, 1H), 10.15 (s, 1H). LCMS (Method-D), retention time 1.54 min, [M+H]214.0.

Intermediate 140: 6-(4-methyl-1H-1,2,3-triazol-1-yl)nicotinaldehyde

Intermediate 140 was prepared (0.25 g, 46.70%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from6-bromonicotinaldehyde (0.50 g, 2.69 mmol) and4-methyl-1H-1,2,3-triazole (0.38 g, 4.03 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.31-2.40 (m, 3H), 8.30 (d, J=8.53 Hz, 1H), 8.44-8.54 (m,1H), 8.70 (s, 1H), 9.10 (d, J=1.51 Hz, 1H), 10.15 (s, 1H). LCMS:(Method-D) retention time: 1.119 min, [M+1]: 189.2.

Intermediate 141: 1-(5-formylpyrimidin-2-yl)-1H-1, 2,4-triazole-3-carbonitrile

Intermediate 141 was prepared (0.25 g, 46.70%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 20 andstarting from 2-chloropyrimidine-5-carbaldehyde (0.50 g, 2.69 mmol) and1H-1,2,4-triazole-3-carbonitrile (0.38 g, 4.03 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.14-81.6 (d, J=8.80 Hz, 1H), 9.13 (s, 2H), 10.18 (s,1H). LCMS (Method-H): retention time 1.27 min, [M+H] 201.2.

Intermediate 142:1-(5-formylpyrimidin-2-yl)-3-methoxy-1H-pyrazole-4-carbonitrile

Intermediate 142 was prepared (1.15 g, 93.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 20 and andstarting from 6-bromonicotinaldehyde (1.00 g, 5.42 mmol) and3-methoxy-H-pyrazole-4-carbonitrile (0.80 g, 6.50 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.07 (s, 3H), 7.95-8.00 (m, 1H), 8.45-8.48 (m, 2H),9.37 (s, 1H), 10.11 (s, 1H). LCMS (Method-D): retention time 2.21 min,[M+H] 229.0.

Intermediate143:3-ethyl-1-(5-formylpyridin-2-yl)-1H-pyrazole-4-carbonitrile

Intermediate 143A: ((E)-2-(ethoxymethylene)-3-oxopentanenitrile

Synthesized according to literature procedures (Australian Journal ofChemistry, 44, 1263-1273, 1991).

Intermediate 143B: 3-ethyl-1H-pyrazole-4-carbonitrile

To a solution of Intermediate 143A (5.00 g, 32.60 mmol) in EtOH (50 mL)was added hydrazine hydrate (5.12 mL, 163 mmol) and the reaction mixturewas stirred at ambient temperature for 1 h. The reaction mixture wasdiluted with water (40 mL) and extracted with 10% MeOH in DCM (2×50 mL).The combined organic layers were washed with brine (20 mL) and driedover anhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by combiflash (Redisep-40 g, 50%EtOAc/n-Hexane) to obtain Intermediate 143B (3.10 g, 78.00%) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (t, J=7.6 Hz, 3H), 2.73 (q,J=7.6 Hz, 2H), 8.16 (s, 1H), 13.4 (br. s, 1H). LCMS (method-L),retention time 0.75 min, [M+H] 122.1.

Intermediate 143

Intermediate 143 was prepared (0.22 g, 68.70%), by using a similarsynthetic protocol as that of Intermediate 20 and starting fromIntermediate 143B (0.19 g, 1.61 mmol) and 6-bromonicotinaldehyde (0.25g, 1.34 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (t, J=7.6 Hz, 3H),2.82 (q, J=7.6 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.47 (dd, J=1.6 Hz,J=8.4 Hz, 1H), 9.03 (s, 1H), 9.43 (s, 1H), 10.12 (s, 1H). LCMS(method-L), retention time 1.18 min, [M+H] 227.1.

Intermediate 144:1-(5-formylpyrimidin-2-yl)-3-methoxy-1H-pyrazole-4-carbonitrile

To a stirring solution of 2-chloropyrimidine-5-carbaldehyde (0.25 g,1.75 mmol) in THE (10 mL) was added 3-methoxy-1H-pyrazole-4-carbonitrile(0.32 g, 2.63 mmol) followed by K₂CO₃ (0.36 g, 2.63 mmol) and theresulting reaction mixture was heated at 70° C. for 1 h. The reactionmixture was cooled to ambient temperature, concentrated to dryness underreduced pressure, diluted with water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography(Redisep-24 g, 0-50% EtOAc/n-hexane) to obtain Intermediate 144 (0.24 g,60.00%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.06 (s, 3H), 9.29 (s, 1H),9.31 (s, 1H), 9.45 (s, 1H), 10.13 (s, 1H). LCMS: The compound did notionize well.

Intermediate 145:3-ethyl-1-(5-formylpyrimidin-2-yl)-1H-pyrazole-4-carbonitrile

Intermediate 145 was prepared (0.23 g, 57.70%) by using similarsynthetic protocol as that of Intermediate 20 and starting fromIntermediate 143B (0.32 g, 2.63 mmol) and2-chloropyrimidine-5-carbaldehyde (0.25 g, 1.75 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.31 (t, J=7.6 Hz, 3H), 2.82 (q, J=3.6 Hz, 2H), 9.34 (s,2H), 9.49 (s, 1H), 10.14 (s, 1H). LCMS (Method-D): retention time 1.55min, [M+18+H] 246.1.

Intermediate 146:3-cyclopropyl-1-(5-formylpyrimidin-2-yl)-1H-pyrazole-4-carbonitrile

Intermediate 146A: 3-cyclopropyl-1H-pyrazole-4-carbonitrile

Synthesized according to literature procedures (PCT Int. Appl.,2015052264).

Intermediate 146 was prepared (0.22 g, 51.90%) as an off-white solid, byusing similar synthetic protocol as that of Intermediate 144 andstarting from 2-chloropyrimidine-5-carbaldehyde (0.25 g, 1.75 mmol) andIntermediate 146A (0.35 g, 2.63 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.99-1.06 (m, 2H), 1.12 (dt, J=8.53, 3.01 Hz, 2H), 2.00-2.20 (m, 1H),9.23-9.36 (m, 2H), 9.46 (s, 1H), 10.14 (s, 1H). LCMS (Method-D):retention time 1.70 min, [M+H] 240.2.

Intermediate 147:3-(difluoromethoxy)-1-(5-formylpyridin-2-yl)-1H-pyrazole-4-carbonitrile

Intermediate 147A:1-(5-formylpyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carbonitrile

To a solution of Intermediate 142 (0.60 g, 2.63 mmol) in DCM (25 mL) wasadded BBr₃ (0.75 mL, 7.89 mmol) at 0° C. and the resulting reactionmixture was stirred at 50° C. for 16 h. The reaction mixture was cooledto ambient temperature, concentrated to dryness under reduced pressureand diluted with water (50 mL). The solid precipitate was filtered anddried under vacuum to obtain Intermediate 147A (0.80 g, crude). LCMS(Method-L): retention time 1.57 min, [M+H] 294.1. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 147

To a stirring solution of Intermediate 147A (0.80 g, 2.71 mmol) in DMF(10 mL) was added sodium chlorodifluoroacetate (0.62 g, 4.07 mmol)followed by Cs₂CO₃ (2.65 g, 8.13 mmol) and the resulting reactionmixture was heated at 100° C. for 3 h. The reaction mixture was cooledto ambient temperature and diluted with water (30 mL). The solidprecipitate was filtered and dried under vacuum to obtain Intermediate12 (0.25 g, 16.41%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 7.33-7.86 (m, 1H), 7.93-8.13 (m, 1H), 8.33-8.63 (m, 1H), 9.03 (dd,J=17.32, 1.76 Hz, 1H), 9.29-9.59 (m, 1H), 10.12 (d, J=9.54 Hz, 1H). LCMS(Method-L): retention time 2.20 min, [M+H] 265.2.

Intermediate 148: 3-(difluoromethyl)-1H-pyrazole-4-carbonitrile

Intermediate 148A: (E)-3-(dimethylamino)acrylonitrile

To a solution of 2-cyanoacetic acid (5.00 g, 58.8 mmol) in 1,4-dioxane(30 mL) was added DMF-DMA (8.66 mL, 64.7 mmol) and the resultingreaction mixture was stirred at ambient temperature for 4 h. Thereaction mixture was cooled to ambient temperature, concentrated todryness under reduced pressure to obtain Intermediate 148A (5.90 gcrude). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.73 (s, 6H) 6.89 (s, 1H) 6.93 (s,1H).

Intermediate 148B:(Z)-2-((dimethylamino)methylene)-4,4-difluoro-3-oxobutanenitrile

To a solution of Intermediate 148A (2.00 g, 20.81 mmol) in toluene (20mL) was added TEA (5.80 mL, 41.6 mmol) followed by 2,2-difluoroaceticacid (1.99 g, 20.81 mmol) at 0° C. Then 20% phosgene in toluene (10 mL,22.89 mmol) was added and resulting reaction mixture was stirred atambient temperature for 1.5 h. The reaction mixture was concentrated todryness under reduced pressure, diluted with saturated NaHCO₃ (120 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine (30 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure to obtain Intermediate 148B (1.70 g,46.90%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.35 (s, 6H),6.31-6.75 (m, 1H), 8.02 (s, 1H). LCMS (Method-0): retention time 0.62min, [M−H] 175.3.

Intermediate 148

Intermediate 148 was prepared (0.65 g, 32.60%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 143B andstarting from Intermediate 148B (1.70 g, 9.76 mmol) and hydrazinehydrate (1.53 mL, 48.80 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.72-7.44(m, 1H), 8.63 (s, 1H), 9.11-9.87 (m, 1H). LCMS (Method-L): retentiontime 1.28 min, [M−H] 141.9.

Intermediate 149-I:(R)-5-(4-((2-chloropyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 149-I was prepared (0.38 g, 80.00%), by using a similarsynthetic protocol as that of Intermediate 143B and starting fromIntermediate 2-I (0.27 g, 1.17 mmol) and2-chloropyrimidine-5-carbaldehyde (0.20 g, 1.40 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.25-2.39 (m, 4H), 2.95 (d, J=11.98 Hz, 3H), 3.52-3.67(m, 1H), 4.17-4.39 (m, 1H), 4.46-4.75 (m, 2H), 4.85 (d, J=10.03 Hz, 1H),5.31-5.50 (m, 2H), 7.67-7.81 (m, 1H), 7.92 (d, J=6.60 Hz, 1H), 8.59-8.77(m, 1H), 8.85 (br. s., 2H), 9.66-9.89 (m, 1H), (1 Exchangeable protonnot observed). LCMS (Method-D): retention time 0.91 min, [M+H] 359.0.

Intermediate150:6-(4-formyl-1H-pyrazol-1-yl)-4-morpholinonicotinonitrile

Intermediate 150A: 4-chloro-6-(4-formyl-H-pyrazol-1-yl)nicotinonitrileand Intermediate 150B:6-chloro-4-(4-formyl-1H-pyrazol-1-yl)nicotinonitrile

Intermediate 150A and 150B was prepared, by using a similar syntheticprotocol as that of Intermediate 15C and starting from4,6-dichloronicotinonitrile (2.50 g, 14.45 mmol) and1H-pyrazole-4-carbaldehyde (1.26 g, 13.14 mmol). First eluted compound,designated as Intermediate 150A, was obtained (0.60 g, 19.63%) as a paleyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (s, 1H), 8.41 (s,1H), 9.12 (s, 1H), 9.39 (s, 1H), 9.99 (s, 1H). Second eluted compound,designated as Intermediate 150B, was obtained (0.40 g, 13.09%) as a paleyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm (400 MHz, DMSO-d₆) δ ppm8.33 (s, 1H), 8.50 (s, 1H), 9.05 (s, 1H), 9.43 (s, 1H), 9.99 (s, 1H).

Intermediate 150

To a solution of Intermediate 150A (0.15 g, 0.65 mmol) in THE (10 mL)was added K₂CO₃ (0.22 mg, 1.61 mmol) followed by morpholine (0.14 g,1.61 mmol) and the resulting reaction mixture was stirred for 16 h. Thereaction mixture was concentrated to dryness under reduced pressure,diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtainIntermediate 150 (0.05 g, 37.00%) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 2.19-2.35 (m, 2H), 2.41 (br. s., 2H), 3.49 (s, 2H),3.77 (d, J=4.52 Hz, 2H), 7.40 (s, 1H), 7.74 (s, 1H), 7.97 (br. s., 1H),8.47 (s, 1H), 8.61 (s, 1H). LCMS (Method-D): retention time 1.89 min,[M+H] 284.0.

Intermediate 151:6-(4-formyl-1H-pyrazol-1-yl)-4-(pyrrolidin-1-yl)nicotinonitrile

Intermediate 151 was prepared (0.08 g, 46.40%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 150 andstarting from Intermediate 150A (0.15 g, 0.65 mmol) and pyrrolidine(0.12 g, 1.61 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.99 (dt, J=6.27,3.39 Hz, 4H), 3.69 (br. s., 4H), 7.11 (s, 1H), 8.30 (s, 1H), 8.49 (s,1H), 9.26 (s, 1H), 9.95 (s, 1H). LCMS (Method-1): retention time 1.09min, [M+1] 268.4.

Intermediate 152:1-(5-formylpyridin-2-yl)-1H-1,2,3-triazole-4-carbonitrile

Intermediate 152A: methyl 6-azidonicotinate

To a stirring solution of methyl 6-fluoronicotinate (9.00 g, 58.00 mmol)in DMF (30 mL) was added sodium azide (3.77 g, 58.0 mmol) and theresulting reaction mixture was heated at 70° C. for 2 h. The reactionmixture was diluted with water (300 mL) and the solid precipitated, wasfiltered and dried under vacuum to obtain Intermediate 152A (6.80 g,65.80%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.96 (s, 3H), 8.20 (dd, J=9.35,1.53 Hz, 1H), 8.30 (m, J=0.98 Hz, 1H), 9.89 (t, J=1.25 Hz, 1H). LCMS(Method-L): retention time 0.73 min, [M+H] 179.1.

Intermediate 152B: methyl6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)nicotinate

To a stirring solution of Intermediate 152A (3.50 g, 19.65 mmol) andprop-2-yn-1-ol (3.30 g, 58.90 mmol) in a mixture of DMF (50 mL) and MeOH(12 mL) was added copper(I) iodide (0.37 g, 1.96 mmol) and stirring wascontinued at 90° C. for 4 h. The reaction mixture was cooled to ambienttemperature, filtered through Celite® and the filtrate was concentratedunder reduced pressure to obtain Intermediate 152B (4.50 g, 98.00%) as abrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.93 (s, 3H), 4.64 (d,J=5.32 Hz, 2H), 5.38 (t, J=5.69 Hz, 1H), 8.27 (d, J=8.56 Hz, 1H), 8.57(dd, J=8.56, 2.20 Hz, 1H), 8.74 (s, 1H), 9.08 (s, 1H). LCMS (Method-O):retention time 0.71 min, [M+H] 235.1.

Intermediate 152C: methyl 6-(4-formyl-1H-1,2,3-triazol-1-yl)nicotinate

To a solution of Intermediate 152B (4.50 g, 11.91 mmol) in acetone (100mL) was added manganese dioxide (10.36 g, 119 mmol) and the resultingreaction mixture was stirred at 60° C. for 16 h. The reaction mixturewas cooled to ambient temperature, concentrated to dryness under reducedpressure, diluted with DCM (250 mL) and filtered through Celite®. Thefiltrate was evaporated under reduced pressure to obtain Intermediate152C (1.90 g, 68.70%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.98 (s, 3H), 8.36 (dd, J=8.53, 0.76 Hz, 1H), 9.08-9.10 (m, 1H), 9.13(dd, J=2.20, 0.73 Hz, 1H), 9.61 (s, 1H), 10.15 (s, 1H). LCMS: Thecompound did not ionize well.

Intermediate 152D: methyl 6-(4-cyano-1H-1,2,3-triazol-1-yl)nicotinate

To a stirring solution of Intermediate 152C (1.90 g, 5.73 mmol) in amixture of pyridine (10 mL) and acetic anhydride (10 mL) was addedhydroxylamine hydrochloride (0.59 g, 8.59 mmol) and the resultingreaction mixture was heated at 110° C. for 2 h. The reaction mixture wascooled to ambient temperature, concentrated to dryness under reducedpressure, diluted with NaHCO₃ solution (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layer was washed with brine (30mL), dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain Intermediate 152_(D) (1.00 g, 76.00%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.94 (s, 3H), 8.34 (d, J=8.50 Hz,1H), 8.65 (dd, J=8.56, 2.20 Hz, 1H), 9.12 (d, J=1.77 Hz, 1H), 9.90 (s,1H). LCMS (Method-L): retention time 1.10 min, [M+H] 230.1.

Intermediate 152E:1-(5-(hydroxymethyl)pyridin-2-yl)-1H-1,2,3-triazole-4-carbonitrile

Intermediate 152E was prepared (0.45 g, 46.50%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 152_(D) (1.00 g, 2.79 mmol) and NaBH₄ (0.53g, 13.96 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.61-4.67 (m, 2H), 5.53(t, J=5.59 Hz, 1H), 8.06-8.17 (m, 2H), 8.58 (m, 1H), 9.79 (s, 1H). LCMS(Method-L): retention time 0.81 min, [M+H] 202.1.

Intermediate 152

Intermediate 152 was prepared (0.18 g, 74.60%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 152E (0.42 g, 1.21 mmol) and Dess-Martinperiodinane (0.51 g, 1.21 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.39(d, J=8.41 Hz, 1H), 8.60 (dd, J=8.44, 2.16 Hz, 1H), 9.16 (dd, J=2.13,0.69 Hz, 1H), 9.92 (s, 1H), 10.19 (s, 1H). LCMS: The compound did notionize well.

Intermediate 153-I and 153-II:4-methyl-5-(5-methylpiperazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 153A: 5-(5-methylpyrazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 153A was prepared (3.20 g, 49.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 2B (7.46 g, 27.2 mmol) and2-chloro-5-methylpyrazine (3.50 g, 27.20 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.32 (s, 3H), 2.60 (s, 3H), 5.50 (s, 2H), 7.70 (d, J=7.53Hz, 1H), 7.81 (d, J=7.53 Hz, 1H), 8.71 (d, J=1.00 Hz, 1H), 8.77 (d,J=1.51 Hz, 1H). LCMS (Method-D): retention time 1.22 min, [M+H] 241.1.

Intermediate 153-I and 153-II

Intermediate 153-I and 153-II was prepared by using a similar syntheticprotocol as that of Intermediate 2-I and 2-I and starting fromIntermediate 153A (3.20 g, 13.32 mmol). The racemate was separated intotwo individual enantiomers by SFC [Chiralpak AD-H (250×4.6 mm) 5 micron;0.2% NH₄OH in MeOH+ACN (1:1), Flow: 1.2 mL/min. Temperature: 30° C., UV:235 nm]. First eluted compound (retention time 3.1 min), designated asIntermediate 153-I, was obtained (0.60 g, 25.00%) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96 (d, J=6.36 Hz, 3H), 2.30 (s, 3H),2.31-2.46 (m, 2H), 2.66-2.74 (m, 1H), 2.86 (dd, J=11.74, 2.69 Hz, 1H),2.95 (dd, J=10.88, 2.81 Hz, 1H), 3.91 (dd, J=9.90, 2.81 Hz, 1H), 5.38(s, 2H), 7.65 (d, J=8.07 Hz, 1H), 7.77 (d, J=8.07 Hz, 1H), (2Exchangeable protons not observed). LCMS (Method-D): retention time 0.56min, [M+H] 247.2. Chiral purity (Method-XXXII): retention time 3.11 min,97.10% ee. Second eluted compound (retention time 4.5 min), designatedas Intermediate 153-II, was obtained (0.55 g, 23.00%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (d, J=6.36 Hz, 3H), 2.30 (s,3H), 2.31-2.46 (m, 2H), 2.66-2.74 (m, 1H), 2.86 (dd, J=11.74, 2.69 Hz,1H), 2.95 (dd, J=10.88, 2.81 Hz, 1H), 3.91 (dd, J=9.90, 2.81 Hz, 1H),5.38 (s, 2H), 7.65 (d, J=8.07 Hz, 1H), 7.77 (d, J=8.07 Hz, 1H), (2Exchangeable protons not observed). LCMS (Method-D): retention time 0.38min, [M+H]247.2. Chiral purity (Method-XXXII): retention time 4.82 min,90.00% ee.

Intermediate 154-I:5-((2R,6S)-1-hydroxy-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 154A-I: tert-butyl(3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a stirring solution of Intermediate 51-I (0.20 g, 0.81 mmol) in DCM(20 mL) was added TEA (0.17 mL, 1.22 mmol) followed by Boc-anhydride(0.23 mL, 0.97 mmol) and stirring was continued at ambient temperaturefor 2 h. The reaction mixture was diluted with 10% NaOH solution (40 mL)and extracted with 10% MeOH in DCM (2×250 mL). The combined organiclayer was washed with brine (30 mL), dried over anhydrous sodium sulfateand evaporated under reduced pressure. The residue was purified bycolumn chromatography (Redisep—24 g, 35% EtOAc/n-hexanes) to obtainIntermediate 154A-I (0.20 g, 71.10%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.05 (s, 3H), 1.48 (s, 9H), 2.33 (s, 4H), 2.75-2.83 (m, 2H), 3.82-3.92(br. s., 1H), 3.94-4.01 (m, 2H), 5.42 (s, 2H), 7.68-7.73 (m, 1H),7.80-7.86 (m, 1H). LCMS (Method-D): retention time 2.42 min, [M+H]347.2.

Intermediate 154B-I: tert-butyl(3S,5R)-4-hydroxy-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a stirred solution of Intermediate 154A-I (0.20 g, 0.57 mmol) in DCM(15 mL) and was added m-CPBA (0.10 g, 0.57 mmol) and the resultingreaction mixture was stirred at ambient temperature for 12 h. Thereaction mixture was concentrated to dryness under reduced pressure andthe residue was purified by preparative HPLC [YMC Triart (150×4.6 mm) 5micron; 0.1% NH₄OH in Water+ACN (1:1), Flow: 1.2 mL/min. Temperature:30° C., UV: 235 nm] to obtain Intermediate 154B-I (0.06 mg, 26.30%). ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6.02 Hz, 3H), 1.43 (s, 9H),2.26-2.36 (m, 3H), 2.68 (d, J=2.01 Hz, 2H), 2.72 (br. s., 1H), 3.80 (d,J=10.54 Hz, 2H), 3.93 (br. s., 1H), 5.42 (s, 2H), 7.68 (d, J=8.03 Hz,1H), 7.79 (d, J=7.53 Hz, 1H), 8.01 (s, 1H). LCMS (Method-D): retentiontime 2.44 min, [M+H] 363.4.

Intermediate 154-I

To a stirring solution of Intermediate 154B-I (0.03 g, 0.08 mmol) in DCM(5 mL) was added 4M HCl in dioxane (0.04 mL, 0.16 mmol) and theresulting reaction mixture was stirred at ambient temperature for 2 h.The reaction mixture was concentrated under reduced pressure. Theresidue was desolved in diethyl ether (100 mL) and the solid precipitatewas filtered and dried under vacuum to obtain Intermediate 154-I (0.02g, 89.00%). LCMS (Method-P) retention time 0.45 min, [M+H] 263.4. Thecompound was taken directly to the subsequent step without furtherpurification or characterization Intermediate 155:4-formyl-4′-methyl-2-oxo-2H-[1,2′-bipyridine]-5′-carbonitrile.

Intermediate 155 was prepared (0.25 g, 25.10%), by using a similarsynthetic protocol as that of Intermediate 6 and starting from2-hydroxyisonicotinaldehyde (0.50 g, 4.06 mmol) and6-bromo-4-methylnicotinonitrile (0.80 g, 4.06 mmol). ¹H NMR (400 MHz,DMSO-d6) δ ppm 2.57 (s, 3H) 6.63-6.66 (m, 1H), 7.21 (d, J=1.60 Hz, 1H),8.05 (t, J=5.2 Hz, 2H), 9.03 (s, 1H), 9.95 (s, 1H), LCMS (Method-D):retention time 2.44 min, [M−H] 238.0.

Intermediate156:6-(4-formyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methylnicotinonitrile

Intermediate 156A: methyl1-(5-cyano-4-methylpyridin-2-yl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

Intermediate 156A was prepared (4.30 g, 79.00%) as a white solid, byusing a similar synthetic protocol as that of Intermediate 15C andstarting from 6-bromo-4-methylnicotinonitrile (4.16 g, 21.11 mmol) andmethyl 2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (3.00 g, 21.11mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54 (s, 3H), 3.79 (s, 3H), 7.89(s, 1H), 8.39 (s, 1H), 8.82 (s, 1H), 11.52 (s, 1H). LCMS (Method-O):retention time 0.88 min, [M+1] 259.1.

Intermediate 156B: methyl1-(5-cyano-4-methylpyridin-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

Intermediate 156B was prepared (1.15 g, 99.00%) as a burgundy solid, byusing a similar synthetic protocol as that of Intermediate 93B andstarting from Intermediate 156A (1.10 g, 4.26 mmol) and iodomethane(2.65 mL, 42.6 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.58 (s, 3H), 3.43(s, 3H), 3.81 (s, 3H), 8.01 (s, 1H), 8.42 (s, 1H), 8.86 (s, 1H). LCMS(Method-O): retention time 1.07 min, [M+1] 273.5.

Intermediate 156C:6-(4-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methylnicotinonitrile

Intermediate 156C was prepared (0.80 g, 69.00%) as a burgundy solid, byusing a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 156B (1.30 g, 4.77 mmol) and NaBH₄ (0.90 g,23.87 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H), 3.24 (s, 3H),4.36 (br.s, 2H), 5.25 (br.s, 1H), 7.28 (s, 1H), 8.45 (s, 1H), 8.79 (s,1H). LCMS (Method-O): retention time 0.69 min, [M+1] 245.4.

Intermediate 156

Intermediate 156 was prepared (0.070 g, crude) as a white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 156C (1.50 g, 6.20 mmol). LCMS (Method-O):retention time 0.92 min, [M+1] 243.5. The compound was taken directly tothe subsequent step without further purification or characterization.

Intermediate157:6-(3-(difluoromethyl)-4-formyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 157A: (3-(difluoromethyl)-1H-pyrazol-4-yl)methanol

Intermediate 157A was prepared (1.40 g, 71.90%), by using a similarsynthetic protocol as that of Intermediate 67A and starting from ethyl3-(difluoromethyl)-1H-pyrazole-4-carboxylate (2.50 g, 13.15 mmol) andDIBAL-H (39.40 mL, 39.40 mmol). ¹H NMR (400 MHz, DMSO-d6) δ ppm 4.48 (d,J 5.02 Hz, 2H), 4.96 (t, J 5.27 Hz, 1H), 6.77-7.15 (m, 1H), 7.72 (s,1H), 13.06 (br. s., 1H). LCMS (Method-D): retention time 0.394 min,[M+H] 149.2.

Intermediate 157B: 3-(difluoromethyl)-1H-pyrazole-4-carbaldehyde

Intermediate 157B was prepared (1.00 g, 50.70%), by using a similarsynthetic protocol as that of Intermediate 152C and starting fromIntermediate 157A (1.00 g, 6.75 mmol) and manganese dioxide (1.17 g,13.50 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.01-7.38 (m, 1H), 8.62 (s,1H), 9.94 (s, 1H), 13.94 (br. s., 1H). LCMS (Method-H): retention time0.54 min, [M−H] 145.0. ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −112.87.

Intermediate 157

Intermediate 157 was prepared (0.50 g, 43.50%), by using a similarsynthetic protocol as that of Intermediate 6 and starting fromIntermediate 157B (0.25 g, 1.71 mmol) and6-bromo-4-methylnicotinonitrile (0.34 g, 1.711 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.66 (s, 3H), 7.30-7.41 (m, 1H), 8.12 (s, 1H), 8.99 (s,1H), 9.50 (s, 1H), 10.04 (s, 1H). LCMS (Method-D): retention time 1.48min, [M−H] 261.0.

Intermediate158:6-(3-cyclopropyl-4-formyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 158A: (3-cyclopropyl-1H-pyrazol-4-yl)methanol

Intermediate 158A was prepared (2.60 g, 67.10%), by using a similarsynthetic protocol as that of Intermediate 157A and starting from ethyl3-cyclopropyl-1H-pyrazole-4-carboxylate (5.00 g, 27.7 mmol). ¹H NMR (400MHz, DMSO-d6) δ ppm 0.78-0.90 (m, 4H), 1.78-1.94 (m, 1H), 4.37 (d,J=5.14 Hz, 2H), 4.65 (t, J=5.26 Hz, 1H), 7.24-7.43 (m, 1H), 12.16 (br.s., 1H). LCMS (Method-H): retention time 0.54 min, [M+H] 208.2.

Intermediate 158B: 3-cyclopropyl-1H-pyrazole-4-carbaldehyde

Intermediate 158B was prepared (1.20 g, 39.30%), by using a similarsynthetic protocol as that of Intermediate 157B and starting fromIntermediate 158A (2.00 g, 14.48 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.78-0.90 (m, 4H), 2.08-2.14 (m, 1H), 7.98-8.19 (m, 1H), 9.90 (s, 1H),(1 Exchangeable proton not observed). LCMS (Method-D): retention time0.57 min, [M+H] 137.1.

Intermediate 158

Intermediate 158 was prepared (0.03 g, 52.90%), by using a similarsynthetic protocol as that of Intermediate 6 and starting fromIntermediate 158B (0.03 g, 1.83 mmol) and6-bromo-4-methylnicotinonitrile (0.04 g, 1.836 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.93-1.12 (m, 4H), 2.50-2.52 (m, 1H), 2.60 (s, 3H), 7.94(s, 1H), 8.91 (s, 1H), 9.27 (s, 1H), 10.05 (s, 1H). LCMS (Method-H):retention time 2.72 min, [M+H] 253.1.

Intermediate 159:1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 159 was prepared (0.10 g, 58.90%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from2-chloropyrimidine-5-carbaldehyde (0.10 g, 0.70 mmol) and4-(trifluoromethyl)-1H-imidazole (0.10 g, 0.77 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.62 (t, J 1.60 Hz, 1H), 8.87 (d, J 1.00 Hz, 1H), 9.36(s, 2H), 10.16 (s, 1H). LCMS (Method-J): retention time 1.80 min, [M+H]243.0.

Intermediate 160:2-(4-formyl-2-methyl-1H-imidazol-1-yl)-4-methoxypyrimidine-5-carbonitrile

To a stirring solution of 2-methyl-1H-imidazole-4-carbaldehyde (0.24 g,2.21 mmol) in ACN (25 mL) was added2-chloro-4-methoxypyrimidine-5-carbonitrile (0.25 g, 1.47 mmol) followedby K₂CO₃ (0.20 g, 1.47 mmol) and stirring was continued at ambienttemperature for 1 h. The reaction mixture was diluted with water (30mL). The solid precipitate was filtered, washed with EtOH (2 mL) anddried under vacuum to obtain Intermediate 160 (0.15 g, crude). LCMS(Method-O): retention time 0.81 min, [M+H]244.1. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 161: 6-(4-formyl-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 161 was prepared (0.30 g, 25.00%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from1H-imidazole-4-carbaldehyde (0.50 g, 5.20 mmol) and6-chloro-4-methoxynicotinonitrile (1.05 g, 6.24 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 4.13 (s, 3H), 7.81 (s, 1H), 8.83 (s, 2H), 8.95 (d, J=1.19Hz, 1H), 9.87 (s, 1H). LCMS (Method-L): retention time 0.75 min, [M+H]229.1.

Intermediate 162: 3-(4-(trimethylstannyl)pyridin-2-yl)oxazolidin-2-one

Intermediate 162A: 3-(4-bromopyridin-2-yl)oxazolidin-2-one

To a stirred solution of 4-bromopyridine-2-amine (5.00 g, 28.90 mmol) inTHE (50 mL) was added 2-chloroethyl chloroformate (4.47 mL, 43.30 mmol)and K₂CO₃ (11.98 g, 87.00 mmol) and the resulting mixture was heated to70° C. for 10 h. The reaction mixture was cooled to ambient temperature,concentrated to dryness under reduced pressure, diluted with water (50mL) and extracted with ethyl acetate (2×100 mL). The combined organiclayer was washed with brine (30 mL), dried over anhydrous sodium sulfateand evaporated under reduced pressure. The residue was purified bycolumn chromatography (Redisep-40 g, 10-20% EtOAc/n-hexane) to obtainIntermediate 162A (1.40 g, 20.00%) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.13-4.20 (m, 2H), 4.44-4.50 (m, 2H), 7.41 (dd,J=5.27, 1.76 Hz, 1H), 8.29 (d, J=5.52 Hz, 1H), 8.30 (d, J=1.51 Hz, 1H).LCMS (Method-D), retention time 1.86 min, [M+H] 243.

Intermediate 162

Intermediate 162 was prepared (0.15 g, crude), by using a similarsynthetic protocol as that of Intermediate 23A and starting fromIntermediate 162A (0.15 g, 0.62 mmol). LCMS (Method-O): retention time1.30 min, [M+1] 328.2. The compound was taken directly to the subsequentstep without further purification or characterization Intermediate 163-Iand 163-II: 5-(piperazin-2-yl)isobenzofuran-1(3H)-one.

Intermediate 163A:5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one

Synthesized according to literature procedures (PCT Int. Appl.,2012037132).

Intermediate 163B: 5-(pyrazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 163B was prepared (3.20 g, 49.00%), by using a similarsynthetic protocol as that of Intermediate 2C and starting fromIntermediate 163A (20.44 g, 79.00 mmol) and 2-chloropyrazine (9.00 g,79.00 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.51 (s, 2H), 8.00 (d,J=8.03 Hz, 1H), 8.35 (dd, J=8.03, 1.51 Hz, 1H), 8.44 (d, J=1.00 Hz, 1H),8.72 (d, J=2.51 Hz, 1H), 8.81 (dd, J=2.51, 1.51 Hz, 1H), 9.38 (d, J=1.51Hz, 1H). LCMS (Method-D): retention time 1.11 min, [M+H] 213.0.

Intermediate 163-I and 163-II

Intermediate 163-I and 163-II was prepared by using a similar syntheticprotocol as that of Intermediate 2-I and 2-II and starting fromIntermediate 163B (5.50 g, 25.90 mmol). The racemate was separated intotwo individual enantiomers by SFC [Lux Amylose-2 (250×4.6 mm) 5 micron;0.4% DEA in EtOH, Flow: 3.0 g/min. Temperature: 30° C., UV: 230 nm].First eluted compound (retention time 1.8 min), designated asIntermediate 163-I, was obtained (0.50 g, 16.70%) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.43 (d, J=11.55 Hz, 1H), 2.61-2.69 (m,1H), 2.72-2.86 (m, 2H), 2.92 (d, J=11.55 Hz, 2H), 3.81 (d, J=8.03 Hz,1H), 5.38 (s, 2H), 7.58 (d, J=8.03 Hz, 1H), 7.68 (s, 1H), 7.78 (d,J=8.03 Hz, 1H), (2 Exchangeable protons not observed). LCMS (Method-D):retention time 0.39 min, [M+H] 219.1. Chiral purity (Method-XVI):retention time 3.11 min, 95.80% ee. Second eluted compound (retentiontime 2.40 min), designated as Intermediate 163-II, was obtained (0.70 g,23.30%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.43 (d,J=11.55 Hz, 1H), 2.61-2.69 (m, 1H), 2.72-2.86 (m, 2H), 2.92 (d, J=11.55Hz, 2H), 3.81 (d, J=8.03 Hz, 1H), 5.38 (s, 2H), 7.58 (d, J=8.03 Hz, 1H),7.68 (s, 1H), 7.78 (d, J=8.03 Hz, 1H), (2 Exchangeable protons notobserved). LCMS (Method-D) retention time 0.53 min, [M+H] 219.1. Chiralpurity (Method-XVI): retention time 4.82 min, 90.00% ee.

Intermediate 164-I and 164-II:4-methyl-5-((2R)-6-methylmorpholin-2-yl)isobenzofuran-1(3H)-one

Intermediate 164A-I:5-((1R)-1-hydroxy-2-((2-hydroxypropyl)amino)ethyl)-4-methylisobenzofuran-1(3H)-one

To a stirring solution of Intermediate 1-I (10.00 g, 52.60 mmol) in EtOH(150 mL) was added 1-aminopropan-2-ol (11.85 g, 158.0 mmol) and stirringwas continued at 50° C. for 16 h. The reaction mixture was concentratedunder reduced pressure and diluted with diethyl ether (50 mL). The solidprecipitate was filtered and dried under vacuum to obtain Intermediate164A-I (8.00 g, 57.40%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96-1.05 (m,3H), 1.98 (br. s., 1H), 2.26 (s, 3H), 2.31-2.43 (m, 1H), 2.55-2.69 (m,1H), 3.47 (br. s., 1H), 4.46 (br. s., 1H), 4.97 (br. s., 1H), 5.38 (d,J=2.01 Hz, 2H), 5.42 (br. s., 1H), 7.65-7.70 (m, 2H), (2 Exchangeableproton not observed). LCMS (Method-O): retention time 0.43 min, [M+H]266.5.

Intermediate 164-I and 164-II

A stirred solution of Intermediate 164A-I (5.00 g, 18.85 mmol) in 63%HBr (50 mL, 921 mmol) in water was heated at 90° C. for 16 h. Thereaction mixture was cooled to ambient temperature, diluted with 10%NaOH solution (100 mL) and extracted with 10% MeOH in DCM (2×250 mL).The combined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thediastereomer was separated into individual isomer by SFC [Chiralpak AD-H(250×4.6 mm) 5 micron; 0.2% NH₄OH in MeOH, Flow: 4.0 g/min. Temperature:30° C., UV: 235 nm]. First eluted compound (retention time 6.20 min),designated as Intermediate 164-I, was obtained (0.80 g, 32.00%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=6.02 Hz, 3H), 2.28 (s, 3H),2.97-3.09 (m, 2H), 3.32 (br. s., 2H), 3.83 (ddd, J=10.42, 6.15, 2.51 Hz,1H), 4.89 (dd, J=10.29, 2.26 Hz, 1H), 5.40 (d, J=3.51 Hz, 2H), 7.61 (d,J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), (1 Exchangeable protons notobserved). LCMS (Method-D) retention time 0.83 min, [M+H] 248.2. Chiralpurity (XXXI): retention time 6.00 min, 99.00% ee. Second elutedcompound (retention time 7.80 min), designated as Intermediate 164-II,was obtained (1.00 g, 40.00%) as off-white solid. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.15 (d, J=6.02 Hz, 3H), 2.28 (s, 3H), 2.97-3.09 (m, 2H),3.32 (br. s., 2H), 3.83 (ddd, J=10.42, 6.15, 2.51 Hz, 1H), 4.89 (dd,J=10.29, 2.26 Hz, 1H), 5.40 (d, J=3.51 Hz, 2H), 7.61 (d, J=8.00 Hz, 1H),7.68 (d, J=8.00 Hz, 1H), (1 Exchangeable protons not observed). LCMS(Method-D) retention time 0.80 min, [M+H]248.2. Chiral purity(Method-XXXII): retention time 7.62 min, 95.00% ee.

Intermediate 165:5-(4-((5-bromopyridin-2-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 165 was prepared (0.18 g, 15.54%), by using a similarsynthetic protocol as that of Intermediate 4 and starting fromIntermediate 2-I (0.19 g, 0.81 mmol) and 5-bromopicolinaldehyde (0.15 g,0.81 mmol). LCMS (Method-D): retention time 1.416 min, [M+2H] 404.0. Thecompound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate 166: 2-(1H-1,2,4-triazol-1-yl)pyrimidine-5-carbaldehyde

Intermediate 166 was prepared (0.30 g, 33.20%), by using a similarsynthetic protocol as that of Intermediate 144 and starting from2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) and4H-1,2,4-triazole (0.266 g, 3.86 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.42 (s, 1H), 9.38 (s, 2H), 9.58 (s, 1H), 10.16 (s, 1H). LCMS(Method-D): retention time 0.43 min, [M+H] 174.2.

Intermediate 167:1-(5-formylpyridin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 167 was prepared (1.15 g, 52.10%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from6-bromonicotinaldehyde (0.30 g, 1.61 mmol) and4-methyl-1H-pyrazole-3-carbonitrile (0.19 g, 1.77 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.25 (d, J 1.00 Hz, 3H), 8.15 (d, J 8.53 Hz, 1H),8.45-8.50 (m, 1H), 8.83 (s, 1H), 9.03-9.07 (m, 1H), 10.14 (s, 1H). LCMS(Method-D): retention time 2.164 min, [M+H] 213.2.

Intermediate 168:1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 168 was prepared (0.30 g, 40.10%), by using a similarsynthetic protocol as that of Intermediate 144 and starting from2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) and4-methyl-1H-pyrazole-3-carbonitrile (0.41 g, 3.86 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.23 (d, J 1.00 Hz, 3H), 8.85 (d, J 1.00 Hz, 1H),8.90 (s, 1H), 9.36 (s, 1H), 10.15 (s, 1H). LCMS (Method-D): retentiontime 1.54 min, [M+H] 214.0.

Intermediate 169:1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 169 was prepared (0.10 g, 58.90%), by using a similarsynthetic protocol as that of Intermediate 144 and starting from2-chloropyrimidine-5-carbaldehyde (0.10 g, 0.70 mmol) and4-(trifluoromethyl)-1H-imidazole (0.11 g, 0.77 mmol). ¹H NMR (400 MHz,DMSO-d6) δ ppm 8.62 (t, J 1.60 Hz, 1H), 8.87 (d, J 1.00 Hz, 1H), 9.36(s, 2H), 10.16 (s, 1H). LCMS (Method-J): retention time 1.80 min, [M+H]243.0.

Intermediate 170:1-(5-formylpyridin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 170 was prepared (0.20 g, 58.40%), by using a similarsynthetic protocol as that of Intermediate 20 and starting from6-bromonicotinaldehyde (0.3 g, 1.61 mmol) and4-methyl-1H-pyrazole-3-carbonitrile (0.19 g, 1.77 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.25 (d, J=1.00 Hz, 3H), 8.15 (d, J=8.53 Hz, 1H),8.45-8.50 (m, 1H), 8.83 (s, 1H), 9.03-9.07 (m, 1H), 10.14 (s, 1H). LCMS(Method-D): retention time 2.16 min, [M+H] 213.2.

Intermediate 171:1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 171 was prepared (0.30, 40.10%), by using a similarsynthetic protocol as that of Intermediate 144 and starting from2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) in4-methyl-H-pyrazole-3-carbonitrile (0.413 g, 3.86 mmol). ¹H NMR (400MHz, DMSO-d6) δ ppm 2.23 (d, J=1.00 Hz, 3H), 8.85 (d, J=1.00 Hz, 1H),8.90 (s, 1H), 9.36 (s, 1H), 10.15 (s, 1H). LCMS (Method-D): retentiontime 1.54 min, [M+H] 214.0.

Intermediate 172:1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 172 was prepared (0.10 g, 58.90%), by using a similarsynthetic protocol as that of Intermediate 144 and starting from2-chloropyrimidine-5-carbaldehyde (0.10 g, 0.70 mmol) and4-(trifluoromethyl)-1H-imidazole (0.10 g, 0.77 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.62 (t, J=1.6 Hz, 1H), 8.87 (d, J=1.00 Hz, 1H), 9.36 (s,2H), 10.16 (s, 1H). LCMS (Method-J), retention time 1.80 min, [M+H]243.0.

Intermediate 173: 6-(1H-1,2,4-triazol-1-yl)nicotinaldehyde

Intermediate 173 was prepared (0.30 g, 49.30%), by using a similarsynthetic protocol as that of Intermediate 138 and starting from6-bromonicotinaldehyde (0.50 g, 2.69 mmol) and 4H-1,2,4-triazole (0.204g, 2.96 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.07 (d, J=8.31 Hz, 1H),8.41 (br. s., 1H), 8.51 (d, J=7.83 Hz, 1H), 9.07 (br. s., 1H), 9.52 (br.s., 1H), 10.15 (br. s., 1H), LCMS (Method-O): retention time 0.62 min,[M+H] 175.2.

Intermediate 174-I:(R)-5-(4-((6-bromopyridin-3-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 174-I was prepared (0.22 g, 24.50%), by using a similarsynthetic protocol as that of Intermediate 4 and starting fromIntermediate 2-I (0.18 g, 0.77 mmol) and 5-bromopicolinaldehyde (0.12 g,0.64 mmol). LCMS (Method-D): retention time 1.02 min, [M+2H] 404.4. Thecompound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate 175:N-(3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4-yl)acetamide

Intermediate 175A: tert-butyl4-amino-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirred solution of Intermediate 4A (0.20 g, 0.58 mmol) in MeOH (20mL) was added ammonium acetate (0.13 g, 1.74 mmol) and stirring wascontinued at ambient temperature for 12 h. To the resulting solution,NaCNBH₄ (0.07 g, 1.16 mmol) was added and stirring was continued atambient temperature for 8 h. The reaction mixture was concentrated todryness under reduced pressure, diluted with saturated solution ofNaHCO₃ (50 mL) and extracted with ethyl acetate (2×40 mL). The combinedorganic layer was washed with brine (30 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The residue was takeninto diethyl ether (30 mL), and solid precipitate was filtered and driedunder vacuum to obtain Intermediate 175A (0.201 g, 99.10%). LCMS(Method-1): retention time 0.91 min, [M−H] 291.5. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 175B: tert-butyl4-acetamido-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirred solution of Intermediate 175A (0.18 g, 0.52 mmol) in DCM(10 mL) was added TEA (0.22 mL, 1.56 mmol) followed by acetyl chloride(0.06 mL, 0.78 mmol) at 0° C. and the resulting reaction mixture wasstirred at ambient temperature for 2 h. The reaction mixture was dilutedwith water (50 mL) and extracted with DCM (3×50 mL). The combinedorganic layers were washed with brine (30 mL), dried over anhydroussodium sulfate and evaporated under reduced pressure. The residue wastaken into diethyl ether (20 mL), and solid precipitate was filtered anddried under vacuum to obtain Intermediate 175B (0.20 g, 99.00%) as ayellow solid. LCMS (Method-1): retention time 1.19 min, [M+1] 387.4. Thecompound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate 175

Intermediate 175 was prepared (0.160 g, crude) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 19-I andstarting from Intermediate 175B (0.15 g, 0.38 mmol)

and TFA (0.300 mL, 3.86 mmol). LCMS (Method-I): retention time 0.38 min,[M+1] 289.6. The compound was taken directly to the subsequent stepwithout further purification or characterization.

Intermediate 176:1-(6-methyl-4-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 176A:1-(4-amino-6-methylpyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 176 was prepared (2.10 g, 64.70%), by using a similarsynthetic protocol as that of Intermediate 6 and starting from1H-pyrazole-4-carbaldehyde (1.54 g, 16.04 mmol) and2-bromo-6-methylpyridin-4-amine (3.00 g, 16.04 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.31 (s, 3H), 6.21-6.26 (m, 2H), 6.97 (d, J=2.01 Hz, 1H),7.62 (s, 1H), 8.19 (s, 1H), 9.15 (s, 1H), 9.94 (s, 1H). LCMS (Method-1):retention time 0.74 min, [M+1] 203.4.

Intermediate 176B: 2-chloroethyl(2-(4-formyl-1H-pyrazol-1-yl)-6-methylpyridin-4-yl)carbamate

Intermediate 176B was prepared (1.10 g, 72.10%), by using a similarsynthetic protocol as that of Intermediate 76A and starting fromIntermediate 176A (1.00 g, 4.95 mmol) and 2-chloroethylcarbonochloridate (0.70 mL, 6.43 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.52 (s, 3H), 3.90-3.93 (m, 2H), 4.41-4.43 (m, 2H), 7.33 (s, 1H), 8.03(s, 1H), 8.26 (s, 1H), 9.24 (s, 1H), 9.96 (s, 1H), 10.59 (s, 1H). LCMS(Method-1): retention time 1.14 min, [M+1] 309.2.

Intermediate 176

Intermediate 176 was prepared (0.60 g, 68.00%), by using a similarsynthetic protocol as that of Intermediate 76B and starting fromIntermediate 176B (1.00 g, 3.24 mmol) and NaH (0.26 g, 6.48 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.54 (s, 3H), 4.14 (dd, J=9.04, 7.03 Hz,2H), 4.52 (dd, J=9.04, 7.03 Hz, 2H), 7.35 (d, J=2.01 Hz, 1H), 8.20 (d,J=1.51 Hz, 1H), 8.29 (s, 1H), 9.28 (s, 1H), 9.97 (s, 1H). LCMS(Method-1): retention time 0.90 min, [M+1] 273.1.

Intermediate 177:1-(6-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 177A: 1-(6-aminopyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 177A was prepared (2.00 g, 51.10%), by using a similarsynthetic protocol as that of Intermediate 6 and starting from1H-pyrazole-4-carbaldehyde (2.00 g, 20.81 mmol) and6-bromopyridin-2-amine (3.60 g, 20.81 mmol). LCMS (Method-1) retentiontime 0.72 min, [M+H] 189.4. The compound was taken directly to thesubsequent step without further purification or characterization.

Intermediate 177B: 2-chloroethyl(6-(4-formyl-1H-pyrazol-1-yl)pyridin-2-yl)carbamate

Intermediate 177B was prepared (0.09 g, 60.00%) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 76A andstarting from Intermediate 177A (0.05 g, 0.27 mmol) and 2-chloroethylcarbonochloridate (0.04 mL, 0.35 mmol). LCMS (Method-1): retention time1.06 min, [M+1] 295.4. The compound was taken directly to the subsequentstep without further purification or characterization Intermediate 177:

Intermediate 177B was prepared (0.01 g, 99.90%) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 76B andstarting from Intermediate 177B (0.08 g, 0.27 mmol) and NaH (0.02 g,0.41 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.20-4.41 (m, 2H), 4.43-4.68(m, 2H), 7.69 (dd, J=6.53, 2.01 Hz, 1H), 7.87-8.16 (m, 2H), 8.33 (s,1H), 9.32 (s, 1H), 9.98 (s, 1H). LCMS (Method-1): retention time 0.92min, [M+1] 259.2.

Intermediate 178:N-(6-(4-formyl-1H-pyrazol-1-yl)pyridin-2-yl)-N-methylmethanesulfonamide

Intermediate 178A:N-(6-(4-formyl-1H-pyrazol-1-yl)pyridin-2-yl)methanesulfonamide

Intermediate 178A was prepared (0.52 g 92.00%) as a yellow solid, byusing a similar synthetic protocol as that of Intermediate 59 andstarting from Intermediate 177A (0.40 g, 2.13 mmol) and mesyl-C1 (0.23mL, 2.76 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.76 (s, 3H), 7.82 (d,J=7.53 Hz, 1H), 8.14 (d, J=9.04 Hz, 1H), 8.25-8.32 (m, 1H), 8.37 (s,1H), 9.40 (s, 1H), 10.00 (s, 1H), (1 Exchangeable proton not observed).LCMS (Method-1): retention time 0.94 min, [M−1] 265.2.

Intermediate 178

Intermediate 178 was prepared (0.150 g, 71.20%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 93B andstarting from Intermediate 178A (0.20 g, 0.75 mmol) and iodomethane(1.07 g, 7.51 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.10 (s, 3H), 3.29(s, 3H), 7.48 (d, J=8.03 Hz, 1H), 7.77 (d, J=8.03 Hz, 1H), 8.08 (t,J=8.03 Hz, 1H), 8.34 (s, 1H), 9.28 (s, 1H), 10.00 (s, 1H). LCMS(Method-1): retention time 0.93 min, [M+1] 281.1.

Intermediate 179:1-(4-(1,1-dioxidoisothiazolidin-2-yl)-6-methylpyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 179A:3-chloro-N-((3-chloropropyl)sulfonyl)-N-(2-(4-formyl-1H-pyrazol-1-yl)-6-methylpyridin-4-yl)propane-1-sulfonamide

Intermediate 179A was prepared (0.85 g, 53.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 59 andstarting from Intermediate 176A (0.40 g, 1.97 mmol) and3-chloropropane-1-sulfonyl chloride (0.70 g, 3.96 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.17 (t, J=7.28 Hz, 4H), 2.64 (s, 3H), 3.71-3.82 (m,4H), 3.86-3.96 (m, 4H), 7.62 (d, J=1.51 Hz, 1H), 7.88 (s, 1H), 8.36 (s,1H), 9.35 (s, 1H), 10.00 (s, 1H). LCMS (Method-1): retention time 1.69min, [M+2H] 485.2.

Intermediate 179B:3-chloro-N-(2-(4-formyl-1H-pyrazol-1-yl)-6-methylpyridin-4-yl)propane-1-sulfonamide

To a solution of Intermediate 179A (0.85 g, 1.76 mmol) in THE (15 mL)was added NaH (0.141 g, 3.52 mmol) and the resulting reaction mixturewas stirred for 4 h. The reaction mixture was diluted with saturatedNH₄Cl solution (50 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was triturated by diethyl ether (30 mL) and dried under vacuumto obtain Intermediate 179B (0.50 g, 83.00%) as a yellow solid. LCMS(Method-1): retention time 1.11 min, [M+H] 343.2. The compound was takendirectly to the subsequent step without further purification orcharacterization.

Intermediate 179

Intermediate 179 was prepared (0.35 g, 79.54%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 76B andstarting from Intermediate 179B (0.50 g, 1.46 mmol) and NaH (0.12 g,2.92 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.40-2.49 (m, 3H), 3.60-3.69(m, 3H), 3.83-3.92 (m, 3H), 7.00 (d, J=1.51 Hz, 1H), 7.62 (d, J=2.01 Hz,1H), 8.28 (s, 1H), 9.27 (s, 1H), 9.97 (s, 1H). LCMS (Method-1):retention time 1.13 min, [M+H] 307.2.

Intermediate 180: (1-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)methylmethanesulfonate

Intermediate 180A: methyl1-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylate

Intermediate 180A was prepared (1.50 g, 86.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 15C andstarting from 4-bromo-2-methoxypyridine (1.31 g, 6.99 mmol) and methyl5-oxopyrrolidine-3-carboxylate (1.00 g, 6.99 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.71-2.90 (m, 2H), 3.69 (s, 3H), 3.84 (s, 3H), 3.97 (dd,J=10.04, 5.52 Hz, 2H), 4.03-4.13 (m, 1H), 7.05 (d, J=2.01 Hz, 1H), 7.36(dd, J=6.02, 2.01 Hz, 1H), 8.09 (d, J=5.52 Hz, 1H). LCMS (Method-1)retention time 0.90 min, [M+H] 251.4.

Intermediate 180B:4-(hydroxymethyl)-1-(2-methoxypyridin-4-yl)pyrrolidin-2-one

Intermediate 180B was prepared (0.85 g, 96.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 180A (1.00 g, 4.00 mmol) and NaBH₄ (0.45 g,11.99 mmol). ¹H NMR (400 MHz, CD₃OD) δ ppm 2.48 (dd, J=16.56, 6.02 Hz,1H), 2.61-2.80 (m, 2H), 3.55-3.69 (m, 2H), 3.73 (dd, J=10.04, 5.52 Hz,1H), 3.91 (s, 3H), 4.00 (dd, J=9.54, 8.03 Hz, 1H), 7.14 (d, J=1.51 Hz,1H), 7.25-7.47 (m, 1H), 8.06 (d, J=6.02 Hz, 1H), (1 Exchangeable protonnot observed). LCMS (Method-I): retention time 0.58 min, [M+H] 223.3.

Intermediate 180

Intermediate 180B was prepared (0.45 g, 83.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 59 andstarting from Intermediate 180B (0.40 g, 1.80 mmol) and mesyl chloride(0.17 mL, 2.16 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.44 (dd, J=17.32,6.78 Hz, 1H), 2.69-2.80 (m, 1H), 2.83-2.95 (m, 1H), 3.02-3.14 (m, 1H),3.16-3.26 (m, 3H), 3.64 (dd, J=10.04, 6.02 Hz, 1H), 3.84 (s, 3H), 3.98(dd, J=10.04, 8.03 Hz, 1H), 4.12-4.44 (m, 1H), 7.05 (d, J=1.51 Hz, 1H),7.24-7.54 (m, 1H), 8.10 (d, J=5.52 Hz, 1H). LCMS (Method-): retentiontime 0.84 min, [M+H] 301.3.

Intermediate 181:(R)-5-(6,6-dimethylmorpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 181A-I:(R)-5-(1-hydroxy-2-((2-hydroxy-2-methylpropyl)amino)ethyl)-4-methylisobenzofuran-1(3H)-one

Intermediate 181A-I was prepared (1.00, 34.70%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 164A-I andstarting from Intermediate 1-I (1.00 g, 5.26 mmol) and1-amino-2-methylpropan-2-ol (1.00 g, 11.22 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.98-1.19 (m, 6H), 2.21-2.32 (s, 3H), 2.60-2.67 (m, 2H),2.70-2.75 (m, 2H), 4.14-4.31 (m, 1H), 4.97-5.12 (m, 1H), 5.34-5.40 (m,2H), 5.42-5.48 (m, 1H), 7.53-7.80 (m, 2H), (1 Exchangeable proton notobserved). LCMS (Method-O): retention time 0.57 min, [M+H] 280.0.

Intermediate I81B-I:(R)-5-(2-(benzyl(2-hydroxy-2-methylpropyl)amino)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one

Intermediate 181B-I was prepared (1.30 g, 38.30%) as a pale yellowsolid, by using a similar synthetic protocol as that of Intermediate 4and starting from Intermediate 181A-I (2.00 g, 7.16 mmol) andbenzaldehyde (0.91 g, 8.59 mmol). LCMS (Method-L): retention time 0.78min, [M+1] 370.

Intermediate I81C-I:(R)-5-(4-benzyl-6,6-dimethylmorpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 181C-I was prepared (0.45 g, 26.90%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 164-I andstarting from Intermediate 181B-I (1.30 g, 3.52 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.20 (s, 3H), 1.43 (s, 3H), 1.75-1.86 (m, 1H), 1.88-2.01(m, 1H), 2.23 (s, 3H), 2.56-2.70 (m, 1H), 2.75-2.97 (m, 1H), 3.43-3.66(m, 2H), 4.97-5.15 (m, 1H), 5.38 (s, 2H), 7.33-7.35 (m, 5H), 7.61-7.65(m, 2H). LCMS (Method-O): retention time 1.67 min, [M+1] 352.4.

Intermediate 181-I

A solution of Intermediate 181B-I (0.40 g, 1.14 mmol) in a mixture ofMeOH (40 mL) and THF (10 mL) was purged with nitrogen for 2 minutes. 10%Pd/C (0.100 g, 0.09 mmol) was added and reaction mixture was stirred atambient temperature for 16 h under H₂ atmosphere. The reaction mixturewas filtered through Celite® and filtrate was concentrated under vacuum.The residue was triturated with diethyl ether (50 mL) and dried undervacuum to obtain Intermediate 181-I (0.350 g, 99.00%) as a pale brownsolid ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (s, 3H), 1.36 (s, 3H), 2.35(s, 3H), 2.50-2.57 (m, 2H), 2.68-2.71 (m, 1H), 2.95 (dd, J=12.80, 2.26Hz, 1H), 4.97 (dd, J=10.54, 2.51 Hz, 1H), 5.38 (s, 2H), 7.50-7.80 (m,2H), (1 Exchangeable proton not observed). LCMS (Method-O): retentiontime 0.81 min, [M+1] 262.4.

Intermediate 182:1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-N-methyl-1H-pyrazole-3-carboxamide

Intermediate 182A: Ethyl1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-1H-pyrazole-3-carboxylate

Intermediate 182A was prepared (0.50 g, 21.05%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 6 andstarting from 6-chloro-4-methoxynicotinonitrile (1.00 g, 5.93 mmol) andethyl 4-formyl-1H-pyrazole-3-carboxylate (1.49 g, 8.90 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.35 (d, J 7.60 Hz, 3H), 4.18 (s, 3H), 4.43 (q,J 7.20 Hz, 2H), 7.79 (s, 1H), 8.88 (s, 1H), 9.19 (s, 1H), 10.26 (s, 1H).LCMS (Method-L): retention time 1.11 min, [M+1] 301.4.

Intermediate 182B:1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-1H-pyrazole-3-carboxylicacid

To a solution of Intermediate 182A (0.30 g, 0.99 mmol) in a mixture ofwater (5 mL) and THE (15 mL) was added LiGH (0.48 g, 1.99 mmol) and theresulting mixture was stirred at ambient temperature for 4 h. Thereaction mixture was concentrated under vacuum and diluted with water(30 mL), acidified with 1N HCl solution and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure to obtain Intermediate 182B (0.30 g, 56.30%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.11 (s, 3H), 7.65 (s, 1H), 8.73(s, 1H), 9.09 (s, 1H), (1H exchangeable proton not observed). LCMS(Method-L): retention time 1.03 min, [M+1] 273.1.

Intermediate 182

To a stirring solution of Intermediate 182B (0.10 g, 0.37 mmol) in DMF(10 mL) was added HATU (280 mg, 0.74 mmol), methanamine HCl (0.12 g,1.84 mmol) followed by TEA (0.26 ml, 1.84 mmol) and the resultingreaction mixture was stirred at ambient temperature for 16 h. Thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (2×25 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure obtain Intermediate 182 (0.20 g, 51.50%) as a brownsolid. LCMS (Method-O): retention time 0.87 min, [M+1] 286.4. Thecompound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate183:1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-1H-pyrazole-3-carboxamide

Intermediate 183 was prepared (0.30 g, 15.05%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 182 andstarting from Intermediate 182B (0.20 g, 0.74 mmol) and ammoniumchloride (0.39 g, 7.35 mmol). LCMS (Method-0): retention time 0.78 min,[M+1] 272. The compound was taken directly to the subsequent stepwithout further purification or characterization.

Intermediate 184:6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-(methoxy-d3)nicotinonitrile

Intermediate 184A: 6-chloro-4-(methoxy-d3) nicotinonitrile

To a stirring solution of CD₃OD (0.20 mL, 5.78 mmol) and NaH (0.116 g,2.89 mmol) in THE (10 mL) was added 4,6-dichloronicotinonitrile (1.00 g,5.78 mmol) in DMA (20 mL) at 0° C. The resulting reaction mixture wasstirred at ambient temperature for 2 h. The reaction mixture was dilutedwith water (30 mL) and extracted with ethyl acetate (2×75 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-24 g, 0-100%EtOAc/n-hexane)) to obtain Intermediate 184A (0.25 g, 25.20%) as anoff-white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.26 (s, 1H), 8.48 (s,1H). LCMS (Method-L): retention time 1.09 min, [M+1]173.1.

Intermediate 184B:6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-(methoxy-d3)nicotinonitrileand Intermediate 184C:6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-4-(methoxy-d3)nicotinonitrile

Intermediate 184B and 184C was prepared, by using a similar syntheticprotocol as that of Intermediate 20 and starting from Intermediate 184A(0.22 g, 1.28 mmol) and Intermediate 28A (0.25 g, 2.56 mmol). Firsteluted compound designated as Intermediate 184B, was obtained (0.12 g,40.00%) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.68 (s,2H), 5.50 (s, 1H), 7.71 (s, 1H), 8.20 (s, 1H), 8.85 (s, 1H). LCMS(Method-O): retention time 0.70 min, [M+1] 235.5. Second eluted compounddesignated as Intermediate 184C, was obtained (0.06 g, 19.98%) as a paleyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.63 (s, 2H), 5.40 (s,1H), 7.89 (s, 1H), 8.72 (s, 1H), 8.90 (s, 1H). LCMS (Method-O):retention time 0.70 min, [M+1] 235.5.

Intermediate 184

Intermediate 184 was prepared (0.05 g, 99.90%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 184B (0.05 g, 0.21 mm) and Dess-martinperiodinane (0.18 g, 0.43 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.01(s, 1H), 8.98 (s, 1H), 9.61 (s, 1H), 10.15 (s, 1H). LCMS: The compounddid not ionize well.

Intermediate 185: 6-(5-methyl-1,2,4-oxadiazol-3-yl)nicotinaldehyde

Intermediate 185A: methyl6-((((1-aminoethyl)amino)oxy)carbonyl)nicotinate

To a solution of 5-(methoxycarbonyl)picolinic acid (0.60 g, 3.31 mmol)in DCM (30 mL) was added oxalyl chloride (0.580 mL, 6.62 mmol) and theresulting reaction mixture was stirred at ambient temperature 1 h. Thereaction was evaporated under reduced pressure. The residue wasredissolved in THE (20 mL) and added TEA (2.31 ml, 16.56 mmol) followedby (E)-N′-hydroxyacetimidamide (0.37 g, 4.97 mmol). The resultingreaction mixture was stirred at ambient temperature 2 h. The reactionmixture was diluted with water (30 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography (Redisep-40g, 0-100% EtOAc/n-Hexane)) to obtain Intermediate 185A (0.18 g, 22.72%)as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.83 (s, 3H),3.93 (s, 3H), 6.47 (br.s, 2H), 8.29 (dd, J 0.80, 8.40 Hz, 1H), 8.42 (dd,J 2.00, 8.00 Hz, 1H), 9.17 (s, 1H). LCMS (Method-L): retention time 0.61min, [M+1] 238.1.

Intermediate 185B: methyl 6-(3-methyl-1,2,4-oxadiazol-5-yl)nicotinate

To a stirring solution of Intermediate 185 (0.15 g, 0.63 mmol) in THF(15 mL) was added 1M solution of TBAF in THE (1.26 mL, 1.26 mmol) andresulting reaction mixture was stirred at ambient temperature for 18 h.The reaction mixture was diluted with water (30 mL) and extracted withethyl acetate (2×25 mL). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography(Redisep-12 g, 0-40% EtOAc/n-hexane) to obtain Intermediate 185B (0.14g, 100%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.59(s, 3H), 4.01 (s, 3H), 8.26 (dd, J 0.80, 8.40 Hz, 1H), 8.49 (dd, J 2.00,8.00 Hz, 1H), 9.38 (s, 1H). LCMS (Method-L): retention time 0.93 min,[M+1] 220.1.

Intermediate 185C:(6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)methanol

Intermediate 185C was prepared (0.10 g, 96.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 185B (0.12 g, 0.55 mmol) and NaBH₄ (0.04 g,1.00 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 4.65 (d, J5.60, 2H), 5.54 (d, J 5.60 Hz, 1H), 7.98 (d, J 6.80 Hz, 1H), 8.19 (d, J8.00 Hz, 1H), 8.74 (s, 1H). LCMS (Method-1) retention time 0.74 min,[M−H] 192.2.

Intermediate 185

Intermediate 185 was prepared (0.10 g, 39.00%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 185C (0.07 g, 0.37 mm) and Dess-Martinperiodinane (0.31 g, 0.73 mmol). LCMS (Method-L): retention time 0.78min, [M+1] 190.0. The compound was taken directly to the subsequent stepwithout further purification or characterization.

Intermediate 186A and 186B: tert-butyl(5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-3-yl)carbamate

Intermediate 186C: tert-butyl (5-bromopyridin-3-yl)carbamate

To a stirring solution of 5-bromonicotinic acid HCl salt (4.00 g, 19.80mmol) in toluene (25 mL) was added TEA (13.80 mL, 99 mmol) followed bydiphenylphosphoryl azide (6.54 g, 23.76 mmol) and the resulting mixturewas heated at 60° C. for 2 h. The reaction mixture was heated at 100° C.after addition of t-butanol (25 mL), for 18 h. The resulting reactionmixture was evaporated under vacuum, diluted with 10% NaHCO₃ solutionand extracted with ethyl acetate (2×100 mL). The combined organic layerwas washed with brine (50 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by columnchromatography (Redisep-40 g, 40-80% EtOAc/n-hexane)) to obtainIntermediate 186C (4.00 g, 74.00%) as a brown solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.49 (s, 9H), 8.17 (s, 1H), 8.29 (d, J 1.60 Hz, 1H), 8.56(d, J 1.60 Hz, 1H), 9.82 (s, 1H). LCMS (Method-L): retention time 1.32min, [M+2] 274.7.

Intermediate 186D: tert-butyl(5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyridin-3-yl)carbamate

To a stirring solution of Intermediate 186C (4.00 g, 14.65 mmol) in amixture of dioxane (100 mL) and water (10 mL) was added Intermediate 2B(4.82 g, 17.57 mmol) and Cs₂CO₃ (9.54 g, 29.3 mmol). The resultingreaction mixture was purged with nitrogen for 10 minutes and Pd(Ph₃P)₄(0.86 g, 0.73 mmol) was added. The resulting reaction mixture was heatedat 100° C. for 18 h and was cooled to ambient temperature. The reactionmixture was filtered through Celite® and the filtrate was concentratedunder vacuum. The resulting residue was purified by columnchromatography (Redisep-40 g, 0-40% EtOAc/n-Hexane)) to obtainIntermediate 186_(D) (5.00 g, 94.00%) as a light brown solid. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.49 (s, 9H), 2.22 (s, 3H), 5.47 (s, 2H), 7.47(d, J 7.60 Hz, 1H), 7.76 (d, J 7.60 Hz, 1H), 7.93 (d, J 2.00 Hz, 1H),8.17 (s, 1H), 8.65 (s, 1H), (1H Exchangeable proton not observed). LCMS(Method-O): retention time 1.12 min, [M+1] 341.5.

Intermediate 186A and 186B

Intermediate 186 was prepared as a brown solid, by using a similarsynthetic protocol as that of Intermediate 118A and starting fromIntermediate 186_(D) (5.00 g, 14.69 mmol). Two diastereomers wereseparated by SFC [Chiralpak ADH (250×4.6 mm) 5 micron; 0.2% NH₄OH inMeOH, Flow: 1.2 mL/min, Temperature: 27° C., UV: 210 nm]. First elutedcompound (retention time 4.08 min), designated as Intermediate 186A:Dia-I, was obtained (0.15 g, 2.96%) as pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.38 (s, 9H), 1.45-1.50 (m, 1H), 1.81-1.96 (m, 1H),2.33 (s, 3H), 2.40-2.45 (m, 2H), 2.78-2.89 (m, 1H), 2.94-3.11 (m, 2H),3.36-3.50 (m, 1H), 5.37 (s, 2H), 6.73-6.75 (m, 1H), 7.38 (d, J=8.30 Hz,1H), 7.64 (d, J=8.30 Hz, 1H). (1 Exchangeable proton not observed). LCMS(Method-O): retention time 0.84 min, [M+1] 347.6. Second eluted compound(retention time 7.99 min), designated as Intermediate 186B: Dia-II, wasobtained (0.12 g, 2.37%) as pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.38 (s, 9H), 1.45-1.50 (m, 1H), 1.81-1.96 (m, 1H), 2.33 (s, 3H),2.40-2.45 (m, 2H), 2.78-2.89 (m, 1H), 2.94-3.11 (m, 2H), 3.36-3.50 (m,1H), 5.37 (s, 2H), 6.73-6.75 (m, 1H), 7.38 (d, J=8.30 Hz, 1H), 7.64 (d,J=8.30 Hz, 1H), (1 Exchangeable proton not observed). LCMS (Method-O):retention time 0.86 min, [M+1] 347.6.

Intermediate 187:(5-(5-cyano-4-methylpyridin-2-yl)-1,2,4-oxadiazol-3-yl)methylmethanesulfonate

Intermediate 187A: 5-cyano-4-methylpicolinic acid

Intermediate 187A was prepared (0.70 g, 76.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 182B andstarting from methyl 5-cyano-4-methylpicolinate (1.00 g, 5.68 mmol) andLiGH (0.27 g, 11.35 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.56 (s, 3H),8.07 (s, 1H), 8.98 (s, 1H), (1H Exchangeable proton not observed). LCMS:(Method-1) retention time: 0.41 min, [M+1]: 163.3.

Intermediate 187B: ethyl5-(5-cyano-4-methylpyridin-2-yl)-1,2,4-oxadiazole-3-carboxylate

To a stirred solution of Intermediate 187A (0.70 g, 4.32 mmol) in EtOAc(25 mL) was added TEA (2.41 mL, 17.27 mmol), ethyl(Z)-2-amino-2-(hydroxyimino)acetate (0.07 g, 5.18 mmol) followed by1-propanephosphonic anhydride (5.49 g, 8.63 mmol) at 0° C. and theresulting reaction mixture was heated at 70° C. for 18 h. The reactionmixture was diluted with water (50 mL) and extracted with EtOAc (3×50mL). The combined organic layers were washed with brine (50 mL), driedover anhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-24 g, 35%EtOAc/n-Hexane) to obtain Intermediate 187B (0.50 g, 44.90%). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.51 (t, J=7.03 Hz, 3H), 2.66-2.77 (s, 3H), 4.59(q, J=7.36 Hz, 2H), 8.39 (s, 1H), 9.00 (s, 1H). LCMS (Method-1)retention time 1.39 min, [M+H] 259.3.

Intermediate 187C:6-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)-4-methylnicotinonitrile

Intermediate 187C was prepared (0.25 g, 42.70%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 60B andstarting from Intermediate 187B (0.70 g, 2.71 mmol) and NaBH₄ (0.20 g,5.42 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.62 (s, 3H), 4.67 (d, J4.60 Hz, 2H), 5.83 (s, 1H), 8.51 (s, 1H), 9.09 (s, 1H). LCMS (Method-1)retention time 0.74 min, [M−H] 217.0.

Intermediate 187

Intermediate 187 was prepared (0.15 g, 6.61%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 59 andstarting from Intermediate 187C (0.25 g, 1.16 mmol) and mesyl chloride(0.09 mL, 1.16 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.37 (s, 3H), 2.73(s, 3H), 5.01 (s, 2H), 7.95 (s, 1H), 8.76 (d, J 4.80 Hz, 1H). LCMS(Method-1): retention time 1.08 min, [M+1] 295.2.

Intermediate 188:1′-methyl-6′-oxo-1′,6′-dihydro-[2,3′-bipyridine]-5-carbaldehyde

Intermediate 188A:1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Intermediate 188A was prepared (0.75 g, 60.00%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 2B andstarting from 5-bromo-1-methylpyridin-2(1H)-one (0.10 g, 0.53 mmol).LCMS (Method-H): retention time 1.08 min, [M+1] 252.2. The compound wastaken directly to the subsequent step without further purification orcharacterization

Intermediate 188

Intermediate 188 was prepared (0.25 g, 24.27%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 188A (0.61 g, 3.27 mmol) and6-bromonicotinaldehyde. LCMS (Method-O): retention time 0.55 min, [M+1]215. The compound was taken directly to the subsequent step withoutfurther purification or characterization.

Intermediate 189-I, II III and IV: tert-butyl3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

Intermediate 189A: methyl5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)nicotinate

Intermediate 189A was prepared (1.30 g, 63.00%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 2C andstarting from Intermediate 2B (2.00 g, 7.30 mmol) and methyl5-bromonicotinate (1.50 g, 6.90 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.25 (s, 3H), 3.99 (s, 3H), 5.33 (s, 2H), 7.43 (d, J 7.60 Hz, 1 H), 7.86(d, J 7.60 Hz, 1H), 8.29 (s, 1H), 8.77 (s, 1H), 9.29 (s, 1H). LCMS(Method-0): retention time 0.68 min, [M+1] 284.1.

Intermediate 189B: methyl5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-3-carboxylate

Intermediate 189B was prepared (1.30 g, 98.00%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 118A andstarting Intermediate 189A (1.30 g, 4.59 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.97-2.06 (m, 1H), 2.08-2.16 (m, 1H), 2.30 (s, 3H),2.68-2.73 (m, 1H), 2.75-2.81 (m, 1H), 2.83-2.92 (m, 1H), 2.97-3.08 (m,1H), 3.11-3.23 (m, 1H), 3.28-3.35 (m, 1H), 3.60 (s, 3H), 5.36 (s, 2H),7.52 (d, J=8.00 Hz, 1H) 7.62 (d, J=8.00 Hz, 1H), (1 Exchangeable protonnot observed). LCMS (Method-O): retention time 0.65 min, [M+1] 290.1.

Intermediate 189C: 1-(tert-butyl) 3-methyl5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1,3-dicarboxylate

Intermediate 189C was prepared (1.00 g, 70.00%), by using a similarsynthetic protocol as that of Intermediate 154A-I and starting fromIntermediate 189B (1.30 g, 4.50 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.42 (s, 9H), 1.97-2.06 (m, 1H), 2.08-2.16 (m, 1H), 2.30 (s, 3H),2.68-2.73 (m, 1H), 2.75-2.81 (m, 1H), 2.83-2.92 (m, 1H), 2.97-3.08 (m,1H), 3.11-3.23 (m, 1H), 3.28-3.35 (m, 1H), 3.60 (s, 3H), 5.36 (s, 2H),7.52 (d, J=8.00 Hz, 1H) 7.62 (d, J=8.00 Hz, 1H), LCMS (Method-1):retention time 1.28 min, [M+H] 390.3.

Intermediate 189-I, II, III and IV

To a stirring solution of Intermediate 189C (2.00 g, 5.14 mmol) in THE(20 mL) was added 2M solution of LiBH₄ in THF (12.84 mL, 25.70 mmol) andthe resulting reaction mixture was heated at 70° C. for 18 h. Thereaction mixture was cooled to ambient temperature, diluted with 10%solution of NH₄Cl (100 mL) and extracted with ethyl acetate (2×100 mL).The combined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theracemate was separated into individual enantiomers by SFC [Chiralpak ADH(250×4.6 mm) 5 micron; 0.2% NH₄OH in MeOH, Flow: 1.2 mL/min,Temperature: 27° C., UV: 210 nm]. First eluted compound (retention time6.12 min), designated as Intermediate 189-I, was obtained (0.12 g,6.50%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s,9H), 1.70-1.79 (m, 1H), 1.77 (br. s., 1H), 1.80 (br. s., 1H), 2.29 (s,3H) 2.64-2.78 (m, 1H), 2.98 (br. s., 1H), 3.39-3.47 (m, 3H), 4.00 (br.s., 1H), 4.20 (br. s., 1H), 4.70 (br. s., 1H), 5.29-5.51 (m, 2H), 7.48(d, J=8.30 Hz, 1H), 7.65 (d, J=8.30 Hz, 1H). LCMS (Method-O): retentiontime 1.04 min, [M+1] 362.4. Second eluted compound (retention time 6.37min), designated as Intermediate 189-II, was obtained (0.04 g, 2.16%) asa pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H),1.70-1.79 (m, 1H), 1.80-1.86 (m., 2H), 2.32 (s, 3H) 2.64-2.78 (m, 1H),2.96-2.99 (m., 1H), 3.39-3.47 (m, 3H), 3.82-3.90 (m., 1H), 3.94-4.16(m., 1H), 4.63 (br. s., 1H), 5.40-5.44 (m, 2H), 7.48 (d, J=8.30 Hz, 1H),7.65 (d, J=8.30 Hz, 1H). LCMS (Method-O): retention time 1.07 min, [M+1]362.4. Third eluted compound (retention time 7.77 min), designated asIntermediate 189-III, was obtained (0.08 g, 4.33%) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H), 1.77-1.92 (m., 3H),2.29 (s, 3H) 2.64-2.78 (m, 1H), 3.05-3.20 (m, 2H), 3.42-3.52 (m, 2H),3.80-4.00 (m, 2H), 4.55 (br. s., 1H), 5.4 (s, 2H), 7.50 (d, J=8.30 Hz,1H), 7.65 (d, J=8.30 Hz, 1H). LCMS (Method-O): retention time 1.04 min,[M+1] 362.4. Fourth eluted compound (retention time 8.38 min),designated as Intermediate 189-IV, was obtained (0.03 g, 1.62%) as apale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H),1.77-1.92 (m, 3H), 2.29 (s, 3H) 2.64-2.78 (m, 1H), 3.05-3.20 (m, 2H),3.42-3.52 (m, 2H), 3.80-4.00 (m., 2H), 4.55 (br. s., 1H), 5.4 (s, 2H),7.50 (d, J=8.30 Hz, 1H), 7.65 (d, J=8.30 Hz, 1H). LCMS (Method-O):retention time 1.07 min, [M+1] 362.4.

Intermediate 190:3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4-ylmethylcarbamate

Intermediate 190A:tert-butyl3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-((methylcarbamoyl)oxy)piperidine-1-carboxylate

To a stirring solution of Intermediate 52A (0.30 g, 0.86 mmol) in THE(25 ml) was added NaH (41.6 mg, 1.73 mmol) followed by CDI (0.21 g, 1.30mmol) at 0° C. and the reaction mixture was stirred at ambienttemperature for 10 minutes. To the resulting reaction mixture was addedmethylamine hydrochloride (0.23 g, 3.46 mmol) and stirring at ambienttemperature was continued for 18 h. The reaction mixture was dilutedwith water (30 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-40 g, 0-80%EtOAc/n-Hexane)) to obtain Intermediate 190A (0.15 g, 43.00%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H), 2.04-2.13 (m, 1H),2.30 (s, 3H), 2.42 (s, 3H), 2.77-3.17 (m, 3H), 3.69-3.95 (m, 1H),3.98-4.19 (m, 2H), 5.07-5.30 (m, 1H), 5.40 (d, J=5.02 Hz, 2H), 6.57-6.90(m, 1H), 7.54 (d, J=8.53 Hz, 1H), 7.68 (d, J=8.53 Hz, 1H). LCMS(Method-O): retention time 1.16 min, [M−56] 349.5.

Intermediate 190

Intermediate 190 was prepared (0.80 g, 0.55 mmol), by using a similarsynthetic protocol as that of Intermediate 38-I and starting fromIntermediate 190A (0.15 g, 0.37 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.04-2.13 (m, 1H), 2.30 (s, 3H), 2.42 (s, 3H), 2.77-3.17 (m, 3H),3.69-3.95 (m, 1H), 3.98-4.19 (m, 2H), 5.07-5.30 (m, 1H), 5.40 (d, J=5.02Hz, 2H), 6.57-6.90 (m, 1H), 7.54 (d, J=8.53 Hz, 1H), 7.68 (d, J=8.53 Hz,1H), (1 Exchangeable proton not observed). LCMS (Method-O): retentiontime 0.44 min, [M+1] 305.5.

Intermediate 191: 4-(5-formyl-2H-tetrazol-2-yl)-2-methylbenzonitrile

Intermediate 191A: ethyl2-(4-cyano-3-methylphenyl)-2H-tetrazole-5-carboxylate

To a stirred solution of 4-amino-2-methylbenzonitrile (1.00 g, 7.57mmol) in a mixture of EtOH (10 mL) and water (10 mL) at 0° C., was addedconc HCl (4.60 mL, 151 mmol) and sodium nitrite (1.04 g, 15.13 mmol).The resulting reaction mixture was stirred for 20 minutes at 0° C. Inanother 50 mL round bottomed flask was added EtOH (20 mL),benzenesulfonohydrazide (1.30 g, 7.57 mmol) followed by ethyl2-oxoacetate (1.545 g, 15.13 mmol) and the mixture was stirred atambient temperature for 1 h. The reaction mixture was evaporated underreduced pressure to obtain (ethyl(E)-2-(2-(phenylsulfonyl)hydrazono)acetate, which was dissolved inpyridine (12.24 mL, 15 mmol) and added into the reaction mixturecontaining first set of the reaction (diazotization). The resultingreaction mixture was stirred at ambient temperature for 18 h. Thereaction mixture was concentrated to dryness under reduced pressure,diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-24 g, 35-55%EtOAc/n-hexane) to obtain Intermediate 191A (0.15 g, 7.71%). ¹H NMR (300MHz, CD₃OD) δ ppm 1.48 (t, J=7.20 Hz, 3H), 2.71 (s, 3H), 4.55 (q, J=6.90Hz, 2H), 8.0 (d, J=8.40 Hz, 1H), 8.22 (m, 1H) 8.33 (s, 1H). LCMS(Method-1) retention time 1.60 min, [M+H] 258.1.

Intermediate 191B:4-(5-(hydroxymethyl)-2H-tetrazol-2-yl)-2-methylbenzonitrile

Intermediate 191B was prepared (0.12 g, 83.00%), by using a similarsynthetic protocol as that of Intermediate 60B and starting Intermediate191A (0.15 g, 0.58 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50 (s, 3H),4.81 (d, J=6.00 Hz, 2H), 5.81 (t, J 6.00 Hz, 1H), 8.09 (s, 2H) 8.25 (s,1H). LCMS (Method-1) retention time 0.97 min, [M+H] 216.4.

Intermediate 191

Intermediate 191 was prepared (0.08 g, 67.30%), by using a similarsynthetic protocol as that of Intermediate 9 and starting Intermediate191B (0.12 g, 0.56 mmol) and Dess-Martin periodinane (0.35 g, 0.84mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.66 (s, 3H), 8.11-8.16 (m, 1H),8.18 (d, J=2.51 Hz, 1H), 8.35 (s, 1H), 10.27 (s, 1H). LCMS (Method-1):retention time 0.87 min, [M−H] 212.0.

Intermediate 192:1-(4-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 192A: 1-(4-aminopyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 192A was prepared (0.40 g, 26.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 6 andstarting from 1H-pyrazole-4-carbaldehyde (0.80 g, 8.33 mmol) and2-bromopyridin-4-amine (1.44 g, 8.33 mmol). ¹H NMR (400 MHz, DMSO-d₆) δppm 6.49-6.53 (m, 3H), 7.12 (d, J=2.01 Hz, 1H), 7.93 (d, J=5.52 Hz, 1H),8.21 (d, J=1.00 Hz, 1H), 9.16 (s, 1H), 9.93 (s, 1H). LCMS (Method-D):retention time 0.73 min, [M+H] 189.1.

Intermediate 192B: 2-chloroethyl(2-(4-formyl-1H-pyrazol-1-yl)pyridin-4-yl)carbamate

Intermediate 192B was prepared (0.20 g, 43.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 76A andstarting from Intermediate 192A (0.30 g, 1.60 mmol) and 2-chloroethylchloroformate (0.27 g, 1.91 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.89-3.93 (m, 2H), 4.41-4.45 (m, 2H), 7.47 (dd, J=5.52, 2.01 Hz, 1H),8.22 (d, J=2.01 Hz, 1H), 8.28 (s, 1H), 8.36 (d, J=6.02 Hz, 1H), 9.27 (s,1H), 9.96 (s, 1H), 10.66 (s, 1H). LCMS (Method-D): retention time 1.92min, [M+H]295.

Intermediate 192

Intermediate 192 was prepared (0.10 g, 56.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 76B andstarting from Intermediate 192B (0.15 g, 0.51 mmol) and NaH (0.02 g,1.018 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.16 (dd, J=8.93, 6.97 Hz,2H), 4.50-4.55 (m, 2H), 7.52 (dd, J=5.75, 2.08 Hz, 1H), 8.31 (s, 2H),8.47 (d, J=5.87 Hz, 1H), 9.31 (s, 1H), 9.97 (s, 1H). LCMS (Method-D):retention time 1.20 min, [M+H] 259.1.

Example 113-I:4,4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)thiazol-2-yl)nicotinonitrile

Example 113-I was prepared (0.02 g, 32.30%) as a white solid, by using asimilar synthetic protocol as that of Intermediate 23B and starting fromIntermediate 55-I (0.20 g, 0.47 mmol) and Intermediate 53 (0.26 g, 0.98mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (s, 3H), 2.25 (s, 3H), 2.50(s, 3H), 2.60 (br. s, 2H), 2.84 (br. s., 2H), 2.98 (br. s., 1H),3.71-3.96 (m, 2H), 4.16 (br. s., 1H), 5.37 (br. s., 2H), 7.65 (m, J=8.00Hz, 1H), 7.79 (d, J=8.00 Hz, 1H), 7.91 (s, 1H), 8.19 (s, 1H), 8.98 (s,1H), (1 Exchangeable proton not observed). LCMS/HPLC (Method-S):retention time 1.69 min, [M+H] 460.2, purity: 100%. (Method-R):retention time 1.25 min, [M+H] 460.2, purity: 96.09%.

Example 114-I:6-(4-((4-hydroxy-4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Example 114-I was prepared by using a similar synthetic protocol as thatof Example 1-I and starting from Intermediate 72 (0.02 g, 0.919 mmol)and Intermediate 6 (0.02 g, 0.707 mmol). The racemate was separated intoindividual enantiomers by SFC [Luxcellulose-2 (250×21.5 mm) 5 micron;0.1% DEA in IPA+ACN (10:90), Flow: 1.0 g/min. Temperature: 30° C., UV:235 nm]. First eluted compound (retention time 7.34 min), designated asExample 114-I, was obtained (0.01 g, 3.86%) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.93 (s, 3H), 1.62 (d, J=13.2 Hz, 1H), 1.79(td, J=12.80, 4.3 Hz, 1H), 2.24 (s, 3H), 2.46-2.39 (m, 1H), 2.59-2.54(m, 4H), 2.64-2.60 (m, 1H), 2.71 (d, J=10.80 Hz, 1H), 3.12 (dd, J=11.20,3.4 Hz, 1H), 3.58-3.50 (m, 2H), 4.34 (br. s., 1H), 5.45-5.23 (m, 2H),7.58 (d, J=7.80 Hz, 1H), 7.88-7.75 (m, 2H), 7.97 (s, 1H), 8.52 (s, 1H),8.83 (s, 1H). HPLC/LCMS (Method-R): retention time 1.14 min, [M+H]458.2, purity: 100%. (Method-S): retention time 1.46 min, [M+H] 458.2,purity: 100%. Chiral purity (Method-XXVIII): retention time 7.34 min,100% ee.

Example 115-I:4-methyl-6-(4-((2-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile

Example 115-I was prepared (0.01 g, 5.86%), by using a similar syntheticprotocol as that of Example 1-I and starting from Intermediate 71-I(0.15 g, 0.61 mmol) and Intermediate 6 (0.10 g, 0.47 mmol). ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.67 (d, J=6.10 Hz, 3H), 2.18 (s, 3H), 2.58 (s, 3H),2.66 (d, J=10.80 Hz, 1H), 3.08-2.86 (m, 3H), 3.17 (d, J=5.10 Hz, 1H),3.61 (br. s., 2H), 4.31 (br. s., 1H), 5.35 (s, 2H), 7.66 (s, 2H), 7.90(s, 1H), 7.99 (s, 1H), 8.56 (s, 1H), 8.84 (s, 1H), (1 Exchangeableproton not observed). LCMS/HPLC (Method-R): retention 1.04 min, [M+H]443.2, purity: 98.77%. (Method-S): retention time 1.46 min, [M+H] 443.2,purity: 98.63%. Chiral purity (Method-V): retention time 7.99 min,97.93% ee.

Example 116-I:6-(4-((4-hydroxy-3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Example 116-I was prepared (0.01 g, 15.60%), by using a similarsynthetic protocol as that of Example 1-I and starting from Intermediate73-I (0.02 g, 0.92 mmol) and Intermediate 6 (0.03 g, 0.14 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.90 (s, 3H), 1.08 (s, 3H), 1.24 (s, 1H), 2.03(t, J=11.10 Hz, 1H), 2.26 (s, 3H), 2.64-2.56 (m, 4H), 2.78 (d, J=10.30Hz, 1H), 3.29 (d, J=4.20 Hz, 1H), 3.54-3.38 (m, 3H), 4.42 (d, J=6.10 Hz,1H), 5.44-5.29 (m, 2H), 7.53 (d, J=8.30 Hz, 1H), 7.63 (d, J=7.80 Hz,1H), 7.84 (s, 1H), 7.99 (s, 1H), 8.51 (s, 1H), 8.84 (s, 1H). HPLC/LCMS(Method-R): retention time 1.12 min, [M+H] 472.3, purity: 96.20%.(Method-S): retention time 1.82 min, [M+H] 472.3, purity: 94.72%. Chiralpurity (Method-V): retention time 4.17 min, 100% ee.

Example 117-I:4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxooxazol-3(2H)-yl)nicotinonitrile

Example 117-I was prepared (0.02 g, 21.10%), by using a similarsynthetic protocol as that of Intermediate 15C and starting fromIntermediate 75 (0.07 g, 0.204 mmol) and 6-bromo-4-methylnicotinonitrile(0.05 g, 0.245 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (d, J=6.10Hz, 3H), 1.24 (s, 1H), 1.95-1.74 (m, 2H), 2.30 (s, 3H), 2.61-2.53 (m,3H), 2.83 (d, J=10.3 Hz, 2H), 2.96 (br. s., 1H), 3.48 (s, 2H), 4.16 (d,J=9.00 Hz, 1H), 5.46-5.30 (m, 2H), 7.66 (d, J=7.80 Hz, 1H), 7.74 (s,1H), 7.81 (d, J=7.80 Hz, 1H), 8.24-8.15 (m, 1H), 8.84 (s, 1H). LCMS/HPLC(Method-R): retention time 0.93 min, [M+H] 460.2, purity: 97.01%.(Method-S): retention time 1.42 min, [M+H] 460.2, purity: 95.11%.

Example 118-I:(R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoimidazolidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile

To a stirring solution of Intermediate 131-I (0.05 g, 0.12 mmol) in THE(10 mL) was added TEA (0.03 mL, 0.25 mmol) followed by CDI (0.03 g, 0.18mmol) and the resulting reaction mixture was heated at 70° C. for 1 h.The reaction mixture was cooled at ambient temperature, diluted withwater (20 mL) and extracted with ethyl acetate (2×40 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydroussodium sulfate and evaporated under reduced pressure. The residue waspurified by HPLC [XBridge C18 (19×150 mm) 5 micron; Solvent A: 0.1% TFA;Solvent B: Acetonitril; Gradient: 10-40% B over 25 minutes, Flow: 15mL/min, retention time 13.72 min, UV: 240 nm] to obtain Example 118-I(0.012 g, 20.41%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H), 2.57(s, 3H), 2.93 (dd, J=8.93, 6.48 Hz, 1H), 3.87 (t, J=8.93 Hz, 1H),4.13-4.34 (m, 2H), 5.06 (t, J=7.09 Hz, 1H), 5.31-5.45 (m, 2H), 7.22 (s,1H), 7.56 (d, J=8.07 Hz, 1H), 7.71 (d, J=8.07 Hz, 1H), 7.80 (s, 1H),7.97 (s, 1H), 8.53 (s, 1H), 8.83 (s, 1H). LCMS/HPLC (Method-S):retention time 1.60 min, [M+H] 429.1, purity: 96.70%. (Method-R):retention time 1.61 min, [M+H] 429.1, purity: 97.92%. Chiral purity(Method-XVIII): retention time 13.72 min, 95.00% ee.

Example 119-I:(R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile

To a stirring solution of Intermediate 131-I (0.06 g, 0.15 mmol) inpyridine (0.50 mL) was added sulfamide (0.30 g, 0.30 mmol) and theresulting reaction mixture was heated at 125° C. for 16 h. The reactionmixture was cooled to ambient temperature, diluted with water (20 mL)and extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine (20 mL), dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was purified by HPLC[Sunfire OBD-C18 (30×250 mm) 5 micron; Solvent A: 10 mM Ammoniumacetate; Solvent B: Acetonitrile; Gradient: 20-50% B over 12 minutes,Flow: 25 mL/min, retention time 17.55 min, UV: 240 nm] to obtain Example119-I (0.02 g, 24.55%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.25 (s, 3H), 2.58 (s, 3H), 2.94 (dd, J=9.90, 7.70 Hz, 1H), 3.92-4.08(m, 2H), 4.20 (d, J=14.43 Hz, 1H), 5.11 (q, J=7.42 Hz, 1H), 5.30-5.43(m, 2H), 7.65-7.78 (m, 2H), 7.91 (s, 1H), 7.98 (s, 1H), 8.14 (d, J=7.09Hz, 1H), 8.65 (s, 1H), 8.84 (s, 1H), LCMS/HPLC (Method-S): retentiontime 1.42 min, [M+H] 465.1, purity: 100%. (Method-R): retention time1.41 min, [M+H] 465.1, purity: 100%. [M+H] 465.1, Chiral purity(Method-XVIII): retention time 17.55 min., 97.25% ee.

Example 120-I:2-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)pyridazin-3(2H)-one

Example 120-I was prepared (0.02 g, 11.00%), by using a similarsynthetic protocol as that of Intermediate 23B and starting from ofIntermediate 96-I (0.15 g, 0.36 mmol) and Intermediate 102 (0.01 g, 0.36mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J 5.90 Hz, 3H),1.68-1.82 (m, 2H), 2.23 (s, 3H), 2.76 (t, J 10.00 Hz, 2H), 2.99 (br. s.,1H), 3.52-3.65 (m, 2H), 3.77 (s, 3H), 4.17 (d, J 9.00 Hz, 1H), 5.27-5.46(m, 2H), 7.07 (d, J 9.80 Hz, 1H), 7.65 (d, J 8.10 Hz, 1H), 7.80 (d, J8.10 Hz, 1H), 7.89 (dd, J 8.20 Hz, 1.6 Hz, 1H), 8.07 (d, J 8.30 Hz, 1H),8.29 (d, J 9.80 Hz, 1H), 8.57 (br. s., 1H), (1 Exchangeable proton notobserved). LCMS/HPLC (Method-S): retention time 1.17 min, [M+H] 446.2,purity: 100%. (Method-R): retention time 0.60 min, [M+H] 446.2, purity:99.60%. Chiral purity (Method-A7): retention time 12.50 min, 100% ee.

Example 121-I:4-methyl-6-(4-(1-((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile(Dia-I:Ena-I) and Example 121-I:4-methyl-6-(4-(1-((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile(Dia-II:Ena-I)

To a stirring solution of Intermediate 101 (0.100 g, 0.325 mmol) in ACN(6 mL) was added Intermediate 2-I (0.08 g, 0.36 mmol) followed by K₂CO₃(0.09 g, 0.65 mmol) and the resulting reaction mixture was stirred atambient temperature for 4 h. The reaction mixture was diluted by ACN (20mL) and filtered through celite. The filtrate was evaporated underreduced pressure and the residue was purified by HPLC [Sunfire OBD(250×30 mm) 5 micron; Solvent A: 10-mM Ammonium acetate; Solvent B:Acetonitrile, Gradient: 30-100% B over 15.5 minutes, retensiontime-12.07, UV: 254 nm] to obtain racemate, which was separated into twoindividual enantiomers by supercritical fluid chromatography (SFC)[Chiralpak OJ-H (250×21 mm) 5 micron; 0.2% NH₄OH in MeOH+ACN (1:1),Flow: 70.0 mL/min. Temperature: 30° C., UV: 290 nm]. First elutedcompound (retention time 5.9 min), designated as Example 121-I, wasobtained (0.02 g, 12.20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.43 (d, J 7.00 Hz, 3H), 1.87 (t, J 10.30 Hz, 1H), 2.12-2.20 (m,1H), 2.26 (s, 3H), 2.61 (s, 3H), 2.75 (d, J 11.00 Hz, 1H), 2.83-2.92 (m,2H), 2.99 (br. s., 1H), 4.07 (d, J 7.00 Hz, 2H), 5.37 (s, 2H), 7.61 (d,J 8.00 Hz, 1H), 7.72 (d, J 8.00 Hz, 1H), 8.09 (s, 1H), 8.21 (s, 1H),8.92 (s, 1H), (1 Exchangeable proton not observed). HPLC (Method-P):retention time 7.92 min, purity: 97.9%. (Method-Q): retention time 6.98min, purity: 98.0%. LCMS (Method-D): retention time 1.73 min, [M+H]444.2. Chiral purity (Method-XX): retention time 4.79 min, 99.5% ee.Second eluted compound (retention time 7.70 min), designated as Example121-II, was obtained (0.02 g, 12.90%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.43 (d, J 7.00 Hz, 3H), 1.87 (t, J 10.30 Hz, 1H),2.12-2.20 (m, 1H), 2.26 (s, 3H), 2.61 (s, 3H), 2.75 (d, J 11.00 Hz, 1H),2.83-2.92 (m, 2H), 2.99 (br. s., 1H), 4.07 (d, J 7.00 Hz, 2H), 5.37 (s,2H), 7.61 (d, J 8.00 Hz, 1H), 7.72 (d, J 8.00 Hz, 1H), 8.09 (s, 1H),8.21 (s, 1H), 8.92 (s, 1H), (1 Exchangeable proton not observed). HPLC(Method-P): retention time 7.83 min, purity: 98.20%. (Method-Q):retention time 7.02 min, purity: 98.8%. LCMS (Method-D): retention time1.84 min, [M+H] 444.2. Chiral purity (Method-XY): retention time 6.34min, 98.60% ee.

Example 122-I:4-methyl-6-(3-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1,2,4-triazol-1-yl)nicotinonitrile

Example 122-I was prepared (0.02 g, 28.40%), by using a similarsynthetic protocol as that of Intermediate 20 and starting fromIntermediate 97 (0.03 g, 0.09 mmol) and 6-bromo-4-methylnicotinonitrile(0.02 g, 0.110 mmol). 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.21-1.35 (m, 3H),2.37 (s, 3H), 2.59-2.70 (m, 4H), 3.14-3.26 (m, 3H), 3.93 (s., 3H), 4.78(br. s., 1H), 5.38-5.56 (m, 2H), 7.80 (d, J 7.80 Hz, 1H), 7.87 (d, J7.80 Hz, 1H), 7.93-8.00 (m, 1H), 8.92-8.99 (m, 1H), 9.59 (s, 1H), (1Exchangeable proton not observed). LCMS/HPLC (Method-S): retention time1.86 min, [M+H] 444.2, purity: 96.60%. (Method-R): retention time 1.19min, [M+H] 444.2, purity: 93.30%. Chiral purity (Method-VI): retentiontime 4.64 min, 100% ee.

Example 123-I:6-(4-((2-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile(Dia-I:Ena-I) and Example 123-II:6-(4-((2-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile(Dia-I:Ena-II)

To solution of 103 (Diastereomer-I) (0.06 g, 0.23 mmol) in ACN (5 mL)was added Intermediate 104 (0.08 g, 0.34 mmol) followed by K₂CO₃ (0.13g, 0.91 mmol) and the resulting reaction mixture was heated at 60° C.for 12 h. The reaction mixture was diluted ACN (20 mL) and filteredthrough celite. The filtrate was evaporated under reduced pressure andthe residue was purified by HPLC [Intersil ODS (250×20 mm) 5 micron;Solvent A: 10 mM Ammonium acetate; Solvent B: Acetonitrile, Gradient:20-100% B over 16 minutes, retention time: 11.8, UV: 220] to obtainracemic mixture, which was separated into two individual enantiomer bysupercritical fluid chromatography (SFC) [Lux amylose-2 (250×21 mm) 5micron; 0.2% NH₄OH in MeOH+Acetonitrile (1:1), Flow: 70.0 mL/min.Temperature: 30° C., UV: 240 nm]. First eluted compound (retention time6.38), designated as Example 123-I, was obtained (0.005 g, 4.60%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.84-1.90 (m, 1H), 2.23(s, 3H), 2.58 (s, 4H), 2.60-2.62 (m, 1H), 2.75 (dd, J 10.79, 2.26 Hz,1H), 3.13 (dd, J 11.55, 3.01 Hz, 1H), 3.44-3.49 (m, 1H), 3.68-3.73 (m,1H), 3.78-3.83 (m, 1H), 3.87 (d, J=15.06 Hz, 1H), 4.01 (d, J 8.03 Hz,1H), 4.70 (t, J 5.27 Hz, 1H), 5.36 (s, 2H), 7.59-7.63 (m, 1H), 7.70 (d,J 8.03 Hz, 1H), 7.83 (s, 1H), 7.98 (s, 1H), 8.53 (s, 1H), 8.82 (s, 1H),(1 Exchangeable proton not observed). HPLC (Method-P): retention time9.77 min, purity: 98.80%. (Method-Q): retention time 7.95 min, purity:97.0%. LCMS (Method-D): retention time 1.55 min, [M+H] 459.2. Chiralpurity (Method-XIII) retention time 7.20 min, 100% ee. Second elutedcompound (retention time 9.20 min), designated as Example 123-II, wasobtained (0.005 g, 4.60%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.84-1.90 (m, 1H), 2.23 (s, 3H), 2.58 (s, 4H), 2.60-2.62(m, 1H), 2.75 (dd, J 10.79, 2.26 Hz, 1H), 3.13 (dd, J 11.55, 3.01 Hz,1H), 3.44-3.49 (m, 1H), 3.68-3.73 (m, 1H), 3.78-3.83 (m, 1H), 3.87 (d, J15.06 Hz, 1H), 4.01 (d, J 8.03 Hz, 1H), 4.70 (t, J 5.27 Hz, 1H), 5.36(s, 2H), 7.59-7.63 (m, 1H), 7.70 (d, J 8.03 Hz, 1H), 7.83 (s, 1H), 7.98(s, 1H), 8.53 (s, 1H), 8.82 (s, 1H), (1 Exchangeable proton notobserved). HPLC (Method-P): retention time 9.96 min, purity: 99.30%.(Method-Q): retention time 8.13 min, purity: 98.70%. LCMS (Method-D):retention time 1.55 min, [M+H] 459.2. Chiral purity (Method-XIII)retention time 10.25 min, 100% ee.

The examples in Table 3 were synthesized using procedures of Example 1-Ito 24-I, 81-I to 84-I and 113-I to 123-I.

HPLC/LCMS Method: LCMS RT (min.), Example Structure Name (M + H)⁺ PurityNMR 125-I

6-(5-(((3R,4R)-4- hydroxy-3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)thiazol-2- yl)-4- methylnicotinonitrile.461.2 S: 1.52, 93.70% R: 1.03, 94.16% ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.60 (br. s., 1 H), 1.92 (br. s., 1 H), 2.15 (t, J = 11.0 Hz, 1 H), 2.24(s, 3 H), 2.32 (d, J = 14.20 Hz, 1 H), 2.65 (s, 3 H), 2.76 (d, J = 9.40Hz, 1 H), 2.97 (d, J = 11.80 Hz, 1 H), 3.08 (t, J = 8.80 Hz, 1 H), 3.76(br. s., 1 H), 3.80-3.96 (m, 2 H), 4.62 (d, J = 5.60 Hz, 1 H), 5.26-5.47(m, 2 H), 7.54 (d, J = 8.00 Hz, 1 H), 7.64 (d, J = 8.00 Hz, 1 H), 7.91(s, 1 H), 8.18 (s, 1 H), 8.97 (s, 1 H). 126-I

5-((2R,6S)-4-((1-(2- methoxypyridin-4-yl)- 1H-imidazol-4- yl)methyl)-6-methylpiperazin-2-yl)- 4- methylisobenzofuran- 1(3H)-one 434.2 S: 1.20,98.20% R: 0.78, 99.82% V: 5.73, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.03 (d, J = 6.1 Hz, 3 H), 1.78 (br. s., 2 H), 2.27 (s, 3 H), 2.84 (br.s., 2 H), 2.97 (br. s., 1 H), 3.47 (br. s., 2 H), 3.90 (s, 3 H), 4.18(br. s, 1 H), 5.38 (s, 2 H), 7.19 (d, J = 1.70 Hz, 1 H), 7.38 (dd, J =2.00, 6.00 Hz, 1 H), 7.66 (d, J = 7.60 Hz, 1 H), 7.73- 7.88 (m, 2 H),8.23 (d, J = 5.60 Hz, 1 H), 8.45 (s, 1 H), (1 Exchangeable proton notobserved). 127-I

5-((2R,6S)-4-((1-(2- (difluoromethyl)pyridin- 4-yl)-1H-pyrazol-4-yl)methyl)-6- methylpiperazin-2-yl)- 4- methylisobenzofuran- 1(3H)-one454.2 S: 1.29, 96.29% R: 0.72, 97.83% ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.03 (d, J = 6.00 Hz, 3 H), 1.64-1.81 (m, 2 H), 2.15-2.32 (m, 3 H), 2.81(d, J = 11.20 Hz, 2 H), 2.98 (br. s., 1 H), 3.49 (s, 2 H), 4.17 (d, J =9.30 Hz, 1 H), 5.28-5.47 (m, 2 H), 7.00 (s, 1 H), 7.65 (d, J = 8.00 Hz,1 H), 7.72-7.88 (m, 2 H), 8.01 (d, J = 5.00 Hz, 1 H), 8.13 (d, J = 1.80Hz, 1 H), 8.61- 8.82 (m, 2 H), (1 Exchangeable proton not observed). ¹⁹FNMR (400 MHz, DMSO-d₆) δ ppm −115.9. 128-I

4-methyl-5-((2R,6S)-6- methyl-4-((1-(2- (trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one472.2 S: 1.16, 96.16% R: 0.92, 96.93% IX: 4.77, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.04 (d, J = 5.60 Hz, 3 H), 1.75 (br. s., 2 H), 2.15-2.31 (m, 3 H), 2.82 (d, J = 8.30 Hz, 2 H), 2.99 (br. s., 1 H), 3.50 (br.s., 2 H), 4.19 (br. s., 1 H), 5.25-5.49 (m, 2 H), 7.66 (d, J = 8.60 Hz,1 H), 7.80 (d, J = 8.10 Hz, 1 H), 7.86 (s, 1 H), 8.14 (dd, J = 2.20,5.60 Hz, 1 H), 8.31 (d, J = 2.00 Hz, 1 H), 8.72-8.88 (m, 2 H), (1Exchangeable proton not observed). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm−66.70. 129-I

1-(difluoromethyl)-4- (4-(((3S,5R)-3-methyl- 5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol-1-yl)pyridin-2(1H)-one 470.2 S: 1.19, 94.05% R: 0.68, 100% XIV: 2.70,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (br. s., 3 H), 1.72 (br.s., 2 H), 2.32 (s, 3 H), 2.80 (br. s., 2 H), 2.85-3.13 (m, 1 H), 3.48(br. s., 2 H), 4.17 (br. s., 1 H), 5.31-5.49 (m, 2 H), 6.87 (d, J = 2.00Hz, 1 H), 7.09 (dd, J = 2.00, 8.00 Hz, 1 H), 7.66 (d, J = 7.50 Hz, 1 H),7.73-7.89 (m, 3 H), 7.89-8.05 (m, 1 H), 8.54-8.66 (m, 1 H), (1Exchangeable proton not observed). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm−102.9. 130-I

1-(5-(((3R,5R)-3- (hydroxymethyl)-5-(4- methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)pyridin-2-yl)-3-methyl-1H- pyrazole-4-carbonitrile 444.2 S: 1.31, 100% R: 0.99,100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J = 6.40 Hz, 3 H),1.72-1.88 (m, 2 H), 2.32 (s, 3 H), 2.55 (s, 3 H), 2.85 (d, J = 10.80 Hz,2 H), 2.98 (d, J = 10.50 Hz, 1 H), 3.55 (s, 2 H), 4.16 (d, J = 8.30 Hz,1 H), 5.38 (d, J = 2.20 Hz, 2 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.81 (d, J= 8.10 Hz, 1 H), 8.19 (s, 1 H), 8.26 (s, 1 H), 9.02 (s, 1 H), (1Exchangeable proton not observed). 131-I

1-(difluoromethyl)-4- (4-(((3S,5R)-3-methyl- 5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-imidazol-1-yl)pyridin- 2(1H)-one 470.2 S: 1.08, 100% R: 0.77, 100% V:2.77, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J = 6.10 Hz, 3H), 1.66-1.85 (m, 2 H), 2.19-2.33 (m, 3 H), 2.83 (d, J = 11.00 Hz, 2 H),2.96 (br. s., 1 H), 3.45 (s, 2 H), 4.16 (d, J = 8.6 Hz, 1 H), 5.29-5.45(m, 2 H), 6.81-6.93 (m, 1 H), 6.97 (dd, J = 2.20, 7.80 Hz, 1 H), 7.64(d, J = 1.20 Hz, 1 H), 7.55-7.72 (m, 1 H), 7.75-7.91 (m, 2 H), 7.99 (d,J = 7.80 Hz, 1 H), 8.47 (s, 1 H), (1 Exchangeable proton not observed).¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −114.90. 132-I

6-(4-(((3R,4R)-4- hydroxy-3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)oxazol-2-yl)- 4-methylnicotinonitrile 445.2S: 1.25, 97.81% R: 0.95 95.67% V: 4.37, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.58-1.70 (m, 1 H), 1.88-1.97 (m, 1 H), 2.16 (t, J = 11.1Hz, 1 H), 2.21-2.32 (m, 4 H), 2.55 (m, 3 H), 2.80 (d, J = 11.70 Hz, 1H), 3.08 (td, J = 3.40, 10.20 Hz, 2 H), 3.56 (s, 2 H), 3.72 (td, J =5.20, 9.8 Hz, 1 H), 4.58 (d, J = 5.60 Hz, 1 H), 5.25-5.46 (m, 2 H), 7.55(d, J = 7.80 Hz, 1 H), 7.64 (d, J = 8.10 Hz, 1 H), 8.19 (s, 1 H), 8.26(s, 1 H), 9.02 (s, 1 H). 133-I

4-methyl-6-(5- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)oxazol-2-yl)nicotinonitrile 444.2 S: 1.51, 100% R: 1.19, 98.32% XI: 6.58 96.51%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (br. s., 3 H), 1.84 (br. s., 2H), 2.28 (s, 3 H), 2.60 (s, 3 H), 2.84 (br. s., 2 H), 2.97 (br. s., 1H), 3.76 (br. s., 2 H), 4.17 (br. s., 1 H), 5.39 (s, 2 H), 7.38 (s, 1H), 7.67 (br. s.,1 H), 7.79 (d, J = 7.80 Hz, 1 H), 8.18 (s, 1 H), 9.02(s, 1 H), (1 Exchangeable proton not observed). 134-I

5-((2R,6S)-4-((1-(6- (difluoromethyl)pyridin- 3-yl)-1H-imidazol-4-yl)methyl)-6- methylpiperazin-2-yl)- 4- methylisobenzofuran- 1(3H)-one454.2 S: 1.15, 100% R: 0.78, 100% VII: 7.80 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.03 (d, J = 6.10 Hz, 3 H), 1.82 (br. s., 2 H), 2.32 (s,3 H), 2.87 (br. s., 2 H), 2.98 (br. s., 1 H), 3.49 (s, 2 H), 4.18 (d, J= 9.00 Hz, 1 H), 5.38 (s, 2 H), 7.02 (s, 1 H), 7.66 (d, J = 7.80 Hz, 1H), 7.72-7.92 (m, 3 H), 8.31 (dd, J = , 2.70, 8.60 Hz, 1 H), 8.38 (d, J= 1.50 Hz, 1 H), 9.07 (d, J = 2.70 Hz, 1 H), (1 Exchangeable proton notobserved). 135-I

(R)-3,4-dimethyl-5-(4- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)benzo[d]oxazol- 2(3H)-one474.1 S: 1.31, 98.71% R: 1.02, 99.80% XIV: 9.78, 98.00% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.71-1.80 (m, 1 H), 1.91 (br. s., 1 H), 2.10 (t, J =9.66 Hz, 1 H), 2.24 (d, J = 4.16 Hz, 6 H), 2.77- 3.06 (m, 4 H),3.41-3.52 (m, 2 H), 3.58 (s, 3 H), 4.06 (d, J = 8.31 Hz, 1 H), 5.38 (s,2 H), 7.08 (d, J = 8.31 Hz, 1 H), 7.28 (d, J = 8.56 Hz, 1 H), 7.58- 7.70(m, 2 H), 7.76-7.83 (m, 2 H). 136-I

(R)-1-(5-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyridin-2- yl)-1H-pyrazole-3- carbonitrile415.1 S: 1.70, 98.44% R: 1.36, 99.60% XVIII: 11.56, 98.10% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.88 (t, J = 10.76 Hz, 1 H), 2.12-2.29 (m, 4H), 2.71-2.85 (m, 2 H), 2.86-3.05 (m, 2 H), 3.57- 3.71 (m, 2 H), 4.10(d, J = 7.58 Hz, 1 H), 5.33- 5.41 (m, 2 H), 7.27 (d, J = 2.69 Hz, 1 H),7.65 (d, J = 7.83 Hz, 1 H), 7.78 (d, J = 7.83 Hz, 1 H), 7.95- 8.07 (m, 2H), 8.46 (s, 1 H), 8.85 (d, J = 2.69 Hz, 1 H), (1 Exchangeable protonnot observed). 137-I

(R)-4-ethoxy-6-(4-((3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)nicotinonitrile. 459.1 S:1.74, 97.53% R: 1.39, 97.64% XVIII: 16.38, 99.23% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.42 (t, J = 6.97 Hz, 3 H), 1.83 (m, 1 H), 2.14 (m, 1 H),2.26 (s, 3 H), 2.81 (d, J = 10.03 Hz, 2 H), 2.87-3.07 (m, 2 H), 3.53 (s,2 H), 4.10 (br. s., 1 H), 4.41 (q, J = 7.09 Hz, 2 H), 5.37 (s, 2 H),7.57 (s, 1 H), 7.65 (d, J = 8.56 Hz, 1 H), 7.76 (d, J = 7.83 Hz, 1 H),7.85 (s, 1 H), 8.52 (s, 1 H), 8.72 (s, 1 H), (1 Exchangeable proton notobserved). 138-I

(R)-1-(5-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyridin-2- yl)-1H-pyrazole-4- carboxamide433.1 S: 1.18, 100% R: 1.00, 100% XVIII: 13.07, 98.77% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.87 (t, J = 10.52 Hz, 1 H), 2.13-2.19 (m, 1 H),2.23 (s, 3 H), 2.78 (dd, J = 17.12, 11.25 Hz, 2 H), 2.87-3.04 (m, 2 H),3.61 (q, J = 13.37 Hz, 2 H), 4.03-4.14 (m, 1 H), 5.35 (s, 2 H), 7.21(br. s., 1 H), 7.65 (d, J = 7.83 Hz, 1 H), 7.75-7.85 (m, 2 H), 7.89-8.01(m, 2 H), 8.12 (s, 1 H), 8.42 (s, 1 H), 9.11 (s, 1 H), (1 Exchangeableproton not observed). 139-I

(R)-5-(4-((2-(2,4- dimethyl-1H-imidazol- 1-yl)pyrimidin-5-yl)methyl)piperazin-2- yl)-4- methylisobenzofuran- 1(3H)-one 419.2 S:1.08, 97.08% R: 0.63, 96.86% XVIII: 14.89, 96.79% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.85-1.92 (m, 1 H), 2.09 (s, 3 H), 2.12-2.20 (m, 1 H),2.24 (s, 3 H), 2.60-2.71 (m, 3 H), 2.78 (t, J = 9.41 Hz, 2 H), 2.85-3.03(m, 2 H), 3.55-3.66 (m, 2 H), 4.08 (d, J = 8.31 Hz, 1 H), 5.36 (d, J =3.18 Hz, 2 H), 7.54 (d, J = 0.98 Hz, 1 H), 7.65 (d, J = 7.83 Hz, 1 H),7.78 (d, J = 7.83 Hz, 1 H), 8.70- 8.80 (m, 2 H), (1 Exchangeable protonnot observed). 140-I

(R)-4-isopropoxy-6-(4- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)nicotinonitrile 473.3 S:1.44, 98.04% R: 1.35, 96.80% XIV: 7.60 99.25% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.39 (d, J = 6.1 Hz, 7 H), 1.80 (t, J = 10.1 Hz, 1 H),2.26 (s, 3 H), 2.80 (d, J = 11.03 Hz, 2H), 2.89 (d, J = 11.03 Hz, 1 H),2.96-3.03 (m, 1 H), 3.47- 3.57 (m, 2 H), 4.07 (d, J = 10.07 Hz, 1 H),5.06 (dt, J = 12.0, 6.0 Hz, 1 H), 5.37 (s, 2 H), 7.57 (s, 1 H), 7.64 (d,J = 8.20 Hz, 1 H), 7.76 (d, J = 8.00 Hz, 1 H), 7.85 (s, 1 H), 8.52 (s, 1H), 8.72 (s, 1 H), (1 Exchangeable proton not observed). 141-I

(R)-4-methyl-5-(4-((4- methyl-6-(4-methyl- 1H-imidazol-1- yl)pyridin-3-yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 418.1 R: 0.99, 100%S: 1.49, 99.12% V: 6.57 99.43% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91(s, 1 H), 2.17 (s, 3 H), 2.21 (s, 3 H), 2.46 (s, 3 H), 2.70-2.77 (m, 3H), 2.85-2.88 (m, 1 H), 2.96-3.02 (m, 1 H), 3.52 (d, J = 7.09 Hz, 2 H),4.00-4.05 (m, 1 H), 5.36 (s, 2 H), 7.62 (s, 2 H), 7.66 (d, J = 8.07 Hz,1 H), 7.80 (d, J = 8.07 Hz, 1 H), 8.21 (s, 1 H), 8.36 (d, J = 1.22 Hz, 1H), (1 Exchangeable proton not observed). 142-I

(R)-4-methyl-5-(4-((2- methyl-6-(4-methyl- 1H-imidazol-1- yl)pyridin-3-yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 418.1 R: 1.01, 99.50%S: 1.55, 99.05% V: 6.65 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.17 (s,3 H), 2.22 (s, 3 H), 2.54 (s, 3 H), 2.67- 2.69 (m, 1 H), 2.70-2.77 (m, 3H), 2.85-2.92 (m, 1 H), 2.96-3.04 (m, 1 H), 3.48-3.55 (m, 2 H),4.02-4.10 (m, 1 H), 5.36 (s, 2 H), 7.45-7.52 (m, 1 H), 7.58-7.67 (m, 2H), 7.77-7.84 (m, 2 H), 8.31-8.42 (m, 1 H), (1 Exchangeable proton notobserved). 143-I

(R)-4,6′-dimethoxy-5′- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-[2,2′- bipyridine]-5- carbonitrile 486.1 R:1.52, 98.06% S: 1.98, 95.85% V: 8.55, 98.56% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.26 (s, 3 H), 2.80 (t, J = 9.90 Hz, 2 H), 2.93-3.03 (m,2 H), 3.57 (d, J = 3.18 Hz, 2 H), 4.03 (s, 4 H), 4.10-4.16 (m, 5 H),5.36 (d, J = 2.45 Hz, 2 H), 7.65 (d, J = 7.83 Hz, 1 H), 7.79 (d, J =8.07 Hz, 1 H), 7.94 (d, J = 7.58 Hz, 1 H), 8.05 (d, J = 7.58 Hz, 1 H),8.11 (s, 1 H), 8.88 (s, 1 H), (1 Exchangeable proton not observed).144-I

(R)-5-(4-((5-fluoro-6- (4-methyl-1H- imidazol-1-yl)pyridin-3-yl)methyl)piperazin- 2-yl)-4- methylisobenzofuran- 1(3H)-one 422.1 R:0.95, 100% S: 1.47, 98.31% XVIII: 14.16, 98.50% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.18 (s, 3 H), 2.25 (s, 2 H), 2.31-2.34 (m, 1 H),2.64-2.70 (m, 2 H), 2.73-2.82 (m, 2 H), 2.88- 2.96 (m, 1 H), 2.97-3.03(m, 1 H), 3.62 (d, J = 3.42 Hz, 2 H), 4.08-4.13 (m, 1 H), 5.37 (d, J =3.42 Hz, 2 H), 7.51 (s, 1 H), 7.66 (s, 1 H), 7.78 (d, J = 8.07 Hz, 1 H),7.92-7.97 (m, 1 H), 8.19 (s, 1 H), 8.29 (s, 1 H), (1 Exchangeable protonnot observed). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −130.24. 145-I

(R)-4-methyl-6-(3- methyl-4-((3-(4- methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile 443.2 R: 1.06, 96.45% S: 1.46, 97.52% V: 8.08,98.28% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.83 (t, J = 10.10 Hz, 1 H),2.17-2.07 (m, 1 H), 2.24 (s, 3 H), 2.32-2.27 (m, 3 H), 2.56 (s, 3 H),2.79 (t, J = 10.6 Hz, 2 H), 2.92-2.84 (m, 1 H), 3.00 (d, J = 11.70 Hz, 1H), 3.51-3.39 (m, 2 H), 4.06 (d, J = 7.60 Hz, 1 H), 4.06 (d, J = 7.60Hz, 1 H), 5.36 (s, 2 H), 7.64 (d, J = 8.10 Hz, 1 H), 7.77 (d, J = 7.80Hz,1 H), 7.90 (s, 1 H), 8.41-8.78 (s, 1 H), (1 Exchangeable proton notobserved). 146-I

(R)-4-methyl-6-(5- methyl-4-((3-(4- methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile 443.2 R: 1.09, 100% S: 1.46, 97.73% V: 8.16, 100%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.95-1.82 (m, 1 H), 2.14 (d, J =13.00 Hz, 1 H), 2.25 (s, 3 H), 2.30 (s, 3 H), 2.56 (s, 3 H), 2.82 (t, J= 10.00 Hz, 2 H), 2.91 (d, J = 14.20 Hz, 1 H), 3.04 (d, J = 11.50 Hz, 1H), 3.54-3.42 (m, 2 H), 4.12 (d, J = 9.00 Hz, 1 H), 5.46-5.27 (m, 2 H),7.66 (d, J = 7.60 Hz, 1 H), 7.77 (d, J = 8.10 Hz,1 H), 7.90 (s, 1 H),8.43 (s, 1 H), 8.78 (s, 1 H), (1 Exchangeable proton not observed).147-I

(R)-4-methyl-5-(4-((6- (4-methyl-1H- imidazol-1-yl)-4-(trifluoromethyl)pyridin- 3- yl)methyl)piperazin-2- yl)isobenzofuran-1(3H)-one 472.1 R: 0.80, 95.13% S: 1.48, 95.42% V: 5.82, 98.48% ee ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.18 (s, 3 H), 2.25 (s, 3 H), 2.35 (m, 2H),2.84 (d, J = 13.40 Hz, 1 H), 3.08 (s, 2 H), 3.16 (br. s., 2 H),3.82-3.69 (m, 2 H), 5.47-5.31 (m, 2 H), 7.76- 7.70 (m, 1 H), 7.83-7.76(m, 2 H), 8.05 (s, 1 H), 8.54 (s, 1 H), 8.81 (s, 1 H), (1 Exchangeableproton not observed). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −59.25, −60.50,−61.47. 148-I

(R)-5-(4-((2-(4,5- dimethyl-1H-imidazol- 1-yl)pyrimidin-5-yl)methyl)piperazin-2- yl)-4- methylisobenzofuran- 1(3H)-one 419.2 R:0.68, 94.87% S: 1.17, 95.02% V: 8.32, 100% ee ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.93-1.87 (m, 1 H), 2.11 (s, 3 H), 2.20-2.13 (m, 1 H), 2.25 (s, 3H), 2.45 (s, 3 H), 2.79 (t, J = 9.70 Hz, 2 H), 2.95-2.86 (m, 1 H),3.03-2.96 (m, 1 H), 3.64-3.53 (m, 2 H), 4.08 (d, J = 9.30 Hz, 1 H),5.43-5.30 (m, 2 H), 7.65 (d, J = 8.30 Hz, 1 H), 7.78 (d, J = 7.80 Hz, 1H), 8.30 (s, 1 H), 8.77 (s, 2 H), (1 Exchangeable proton not observed).149-I

(R)-5-(4-((4-methoxy- 6-(4-methyl-1H- imidazol-1-yl)pyridin-3-yl)methyl)piperazin- 2-yl)-4- methylisobenzofuran- 1(3H)-one 434.2 R:0.64, 100% S: 1.08, 100% XII: 2.71, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 1.94-1.85 (m, 1 H), 2.17 (s, 4 H), 2.26 (s, 3 H), 2.78 (d, J = 10.30Hz, 2 H), 2.91 (d, J = 7.80 Hz, 1 H), 3.01-2.95 (m, 1 H), 3.52 (s, 2 H),3.94 (s, 3 H), 4.07 (br. s., 1 H), 5.37 (s, 2 H), 7.29 (s, 1 H), 7.64(d, J = 8.10 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J = 8.30 Hz, 1 H), 8.21(s, 1 H), 8.42 (s, 1 H), (1 Exchangeable proton not observed). 150-I

(R)-5-(4-((2-(5- (difluoromethyl)-4- methyl-1H-imidazol-1-yl)pyrimidin-5- yl)methyl)piperazin-2- yl)-4- methylisobenzofuran-1(3H)-one 455.3 S: 1.23, 97.70% R: 0.95, 99.03% XVIII: 6.04, 100% ee ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.37-2.33 (m, 3 H), 2.59-2.53 (m, 2 H),2.63 (t, J = 2.10 Hz, 3 H), 3.08 (d, J = 10.50 Hz, 2H), 3.43 (br. s., 2H), 3.79 (s, 2 H), 4.73 (br. s., 1 H), 5.42 (s, 1 H), 5.46 (s, 1 H),7.14-7.00 (m, 1 H), 7.77 (d, J = 8.10 Hz, 1 H), 7.86 (d, J = 7.80 Hz, 1H), 8.47 (s, 1 H), 8.89 (s, 2 H), (1 Exchangeable proton not observed).¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −110.99. 151-I

4,6-dimethyl-2-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2H-1,2,3- triazol-2-yl)pyrimidine-5- carbonitrile 459.2 R: 0.95, 97.35% S: 1.19, 100% XXV:7.12, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J = 5.60 Hz, 3H), 1.82 (br. s., 2 H), 2.28 (s, 3 H), 2.76-2.66 (m, 6 H), 2.81 (br. s.,2 H), 2.99 (br. s., 1 H), 3.78 (s, 2 H), 4.19 (br. s., 1 H), 5.46-5.30(m, 2 H), 7.67 (d, J = 7.60 Hz, 1 H), 7.80 (d, J = 8.30 Hz, 1 H), 8.24(s, 1 H), (1 Exchangeable proton not observed). 152-I

3-(3-methyl-5-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)phenyl)oxazolidin- 2-one 502.2 S: 1.42, 100% R: 0.90, 100% ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.03 (d, J = 6.50 Hz, 3 H), 1.79-1.64 (m, 2 H),2.32-2.18 (m, 3 H), 2.43-2.35 (m, 3 H), 2.81 (d, J = 11.00 Hz, 2 H),2.97 (br. s., 1 H), 3.48 (s, 2 H), 4.24-4.03 (m, 3 H), 4.56-4.40 (m, 2H), 5.38 (s, 2 H), 7.30 (s, 1 H), 7.42 (s, 1 H), 7.69-7.58 (m, 2 H),7.80 (d, J = 8.00 Hz, 1 H), 7.90-7.84 (m, 1 H), 8.37 (s, 1 H), (1Exchangeable proton not observed). 153-I

(R)-4-methyl-5-(4-((6- (4-methyl-1H- imidazol-1- yl)pyridazin-3-yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 405.4 S: 1.13, 95.04%R: 0.75, 95.90% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.90-2.01 (m, 1 H), 2.20(s, 3 H), 2.24 (s, 3 H), 2.27-2.34 (m, 2 H), 2.73-2.80 (m, 2 H), 2.89-3.03 (m, 2 H), 3.85 (d, J = 5.32 Hz, 2 H), 4.05- 4.10 (m, 1 H),5.31-5.41 (m, 2 H), 7.65 (d, J = 8.13 Hz, 1 H), 7.74-7.80 (m, 2 H), 7.93(d, J = 8.93 Hz, 1 H), 8.12 (d, J = 9.05 Hz, 1 H), 8.51 (s, 1 H). 154-I

4-methoxy-6-(3-(((R)- 3-(4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrrolidin-1- yl)nicotinonitrile(Diastereomer-I) 448.2 G: 9.96, 95.87% F: 8.77, 96.16% XIII: 3.39, 100%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.06 (m, 1 H), 1.73-1.81 (m, 2H), 2.04- 2.14 (m, 2 H), 2.31 (s, 3 H), 2.34-2.40 (m, 3 H), 2.44-2.48(m, 2 H), 2.53-2.62 (m, 1 H), 2.78- 3.02 (m, 4 H), 3.92 (s, 3 H),4.03-4.10 (m, 1 H), 5.38 (d, J = 5.77 Hz, 2 H), 6.00 (s, 1 H), 7.65 (d,J = 8.03 Hz, 1 H), 7.80 (d, J = 8.09 Hz, 1 H), 8.26 (s, 1 H), 8.55-8.56(m, 1 H). 155-I

4-methoxy-6-(3-(((R)- 3-(4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrrolidin-1- yl)nicotinonitrile(Diastereomer-II) 448.2 F: 8.09 96.88% G: 10.05, 96.44% XIII: 4.72,97.82% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79-1.86 (m, 2 H), 2.02-2.08(m, 1 H), 2.30 (s, 3 H), 2.34-2.39 (m, 4 H), 2.76-2.81 (m, 2 H),2.84-2.93 (m, 5 H), 2.95-3.01 (m, 1 H), 3.39- 3.46 (m, 1 H), 3.92 (s, 3H), 4.07 (d, J = 9.79 Hz, 1 H), 5.38 (d, J = 4.14 Hz, 2 H), 6.00 (s, 1H), 7.65 (d, J = 8.09 Hz, 1 H), 7.80 (d, J = 7.91 Hz, 1 H), 8.25 (s, 1H). 156-I

4-methyl-6-(3-(((R)-3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrrolidin-1- yl)nicotinonitrile(Diastereomer-I) 432.2 F: 9.61 96.97% G: 10.62, 97.28% XIII: 3.05,99.92% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79-1.86 (m, 2 H), 2.00-2.14(m, 3 H), 2.30 (s, 3 H), 2.33 (m, 4 H), 2.34-2.39 (m, 2 H), 2.53- 2.61(m, 1 H), 2.77-2.93 (m, 4 H), 2.94-3.01 (m, 1 H), 3.35-3.46 (m, 2 H),4.06 (d, J = 7.91 Hz, 1 H), 5.38 (d, J = 5.96 Hz, 2 H), 6.46 (s, 1 H),7.65 (d, J = 7.97 Hz, 1 H), 7.79 (d, J = 7.91 Hz, 1 H), 8.36 (s, 1 H).157-I

4-methyl-6-(3-(((R)-3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrrolidin-1- yl)nicotinonitrile(Diastereomer-II) 432.2 F: 9.60 97.43% G: 10.59, 97.53% XIII: 3.86,95.66% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.16 (m, 1 H), 1.79-1.87(m, 1 H), 2.30 (s, 3 H), 2.33 (m, 5 H), 2.33-2.37 (m, 3 H), 2.53- 2.61(m, 1 H), 2.77-2.93 (m, 4 H), 2.94-3.01 (m, 1 H), 3.08-3.15 (m, 1 H),3.35-3.46 (m, 2 H), 4.06 (d, J = 7.91 Hz, 1 H), 5.38 (d, J = 3.95 Hz, 2H), 6.46 (s, 1 H), 7.65 (d, J = 8.16 Hz, 1 H), 7.79 (d, J = 8.03 Hz, 1H), 8.36 (s, 1 H). 158-I

4-methyl-6-(4-(((R)-3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-2- oxopyrrolidin-1- yl)nicotinonitrile(Diastereomer-II) 446.2 F: 9.97 95.67% G: 12.43, 96.68% XIII: 4.57,98.7% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.20 (m, 1 H), 1.80-1.90(m, 1 H), 2.00- 2.10 (m, 1 H), 2.29-2.35 (m, 3 H), 2.45-2.58 (m, 2 H),2.54-2.58 (m, 5 H), 2.65-2.90 (m, 5 H), 3.70-3.80 (m, 1 H), 4.05-4.15(m, 2 H), 5.39 (d, J = 4.65 Hz, 2 H), 7.66 (d, J = 8.13 Hz, 1 H), 7.80(d, J = 8.31 Hz, 1 H), 8.37 (s, 1 H), 8.78 (s, 1 H). 159-I

4-methoxy-6-(4-(((R)- 3-(4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-2- oxopyrrolidin-1- yl)nicotinonitrile(Diastereomer-I) 462.3 S: 1.22 97.06% R: 0.97, 96.87% XIII: 5.20, 97.50%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.85-1.93 (m, 1 H), 2.07-2.11 (m, 1H), 2.30 (s, 3 H), 2.37-2.45 (m, 2 H), 2.69-2.81 (m, 3 H), 2.84-2.96 (m,2 H), 2.98-3.05 (m, 3 H), 3.47- 3.57 (m, 2 H), 3.72-3.78 (m, 3 H),4.07-4.15 (m, 1 H), 5.38 (d, J = 3.91 Hz, 2 H), 7.66 (d, J = 7.83 Hz, 1H), 7.78 (d, J = 8.01 Hz, 1 H), 8.16 (s, 1 H), 8.64 (s, 1 H). 160-I

4-methyl-6-(5-(((R)-3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-2- oxooxazolidin-3- yl)nicotinonitrile(Diastereomer-II) 448.2 Q: 8.61, 94.33% D: 1.67, 99.28% ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.99 (s, 1 H), 2.29 (s, 3 H), 2.46-2.48 (m, 3 H),2.59-2.62 (m, 2 H), 2.71-2.75 (m, 3 H), 2.81- 2.87 (m, 4 H), 3.80-3.89(m, 1 H), 3.90-3.96 (m, 1 H), 4.23-4.29 (m, 1 H), 5.40 (s, 2 H), 7.66(d, J = 7.72 Hz, 1 H), 7.80 (d, J = 8.03 Hz, 1 H), 8.16 (s, 1 H), 8.78(s, 1 H). 161-I

4-methyl-5-((2R,6S)-6- methyl-4-((1-(5- (methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one482.2 S: 1.26, 95.63%. R: 0.85, 96.50%. XVIII: 17.07, 100% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.04 (d, J = 6.10 Hz, 3 H), 1.74 (br. s., 2 H),2.27 (s, 3 H), 2.82 (d, J = 8.30 Hz, 2 H), 2.98 (br. s., 1 H), 3.35 (s,3 H), 3.55 (br. s., 2 H), 4.18 (br. s., 1 H), 5.46-5.27 (m, 2 H), 7.66(d, J = 7.80 Hz, 1 H), 7.80 (d, J = 7.80 Hz, 1 H), 7.87 (s, 1 H), 8.10(d, J = 8.80 Hz, 1 H), 8.46 (dd, J = 8.80, 2.40 Hz, 1 H), 8.58 (s, 1 H),8.93 (d, J = 2.20 Hz, 1 H), (1 Exchangeable proton not observed). 162-I

4-(4-(((3R,4R)-4- hydroxy-3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H- imidazol-1-yl)-2- methoxybenzonitrile459.2 S: 1.19, 100% R: 0.97, 100% XXIX: 3.00, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.96 (br. s., 1 H), 2.13-2.43 (m, 4 H), 2.74 (m, 1 H),2.79-3.07 (m, 2 H), 3.07-3.20 (m, 2 H), 3.82 (br. s., 1 H), 3.94-4.12(m, 4 H), 4.68 (br. s., 1 H), 5.36 (br. s., 2 H), 7.46-7.56 (m, 4 H),7.61-7.79 (m, 2 H), 7.94-8.13 (m, 1 H), (1 Exchangeable proton notobserved). 163-I

6-(4-(((3R,4R)-4- hydroxy-3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H- imidazol-1-yl)-4- methylnicotinonitrile444.5 P: 4.27, 98.40% Q: 5.59, 98.86% ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.60-1.80 (m, 1 H), 1.92-1.97 (m, 1 H), 2.23- 2.30 (m, 1 H), 2.35 (S, 3H), 2.76-2.91 (m, 3 H), 2.95-3.16 (m, 2 H), 3.44-3.61 (m, 2 H), 3.65-3.80 (m, 2 H), 4.51 (s, 1 H), 5.37 (d, J = 6.40 Hz, 2 H), 7.54 (d, J =8.03 Hz, 1 H), 7.64 (d, J = 7.91 Hz, 1 H), 7.85 (br. s., 1 H), 8.00 (s,2 H), 8.55 (br. s., 1 H), 8.86 (s, 1 H). 164-I

4-methyl-2-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H- imidazol-1-yl)pyrimidine-5- carbonitrile 444.3 S: 1.32 100% R: 0.98, 96.43% XXIX:3.45, 93.48% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J = 6.10 Hz, 3H), 1.88-1.71 (m, 2 H), 2.20-2.32 (m, 3 H), 2.67-2.74 (m, 3 H),2.76-2.88 (m, 2 H), 2.96 (ddd, J = 9.60, 6.50, 2.70 Hz, 1 H), 3.52 (s, 2H), 4.16 (dd, J = 10.00, 2.20 Hz, 1 H), 5.47-5.29 (m, 2 H), 7.65 (d, J =7.80 Hz, 1 H), 7.89-7.75 (m, 2 H), 8.56 (d, J = 1.20 Hz, 1 H), 9.22 (s,1 H), (1 Exchangeable proton not observed). 165-I

4-methyl-5-((2R,6S)-6- methyl-4-((6′- (methylsulfonyl)-[2,3′-bipyridin]-5- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 493.2S: 1.27, 99.27% R: 0.81, 98.46% XXIX: 9.99, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.03 (d, J = 6.40 Hz, 3 H), 1.64-1.88 (m, 2 H), 2.25 (s,3 H), 2.99 (br. s., 2 H), 2.79 (d, J = 10.30 Hz, 2 H), 3.34 (s, 3 H),3.64 (s, 2 H), 4.19 (d, J = 9.50 Hz, 1 H), 5.46-5.28 (m, 2 H), 7.66 (d,J = 8.10 Hz, 1 H), 7.81 (d, J = 8.10 Hz, 1 H), 7.93 (dd, J = 8.10, 2.00Hz, 1 H), 8.09-8.25 (m, 2 H), 8.70 (d, J = 1.70 Hz, 1 H), 8.78 (dd, J =8.10, 2.20 Hz, 1 H), 9.39-9.49 (m, 1H). 166-I

4-methoxy-2-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2H-1,2,3- triazol-2-yl)pyrimidine-5- carbonitrile 461.3 P: 6.75, 95.94% Q: 8.64, 96.38% V:5.85, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J = 6.21 Hz, 3H), 1.77-1.87 (m, 2 H), 2.26 (s, 3 H), 2.80 (d, J = 10.60 Hz, 2 H),2.94- 3.01 (m, 1 H), 3.77 (s, 2 H), 4.17-4.19 (m, 4 H), 5.37 (d, J =3.01 Hz, 2 H), 7.65 (d, J = 7.97 Hz, 1 H), 7.79 (d, J = 7.97 Hz, 1 H),8.25 (s, 1 H), 9.15 (s, 1 H), (1 Exchangeable proton not observed).167-I

4-methoxy-2-(2- methyl-4-(((3S,5R)-3- methyl-5-(4-methyl-1- oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H- imidazol-1-yl)pyrimidine-5- carbonitrile 474.3 Q: 9.51, 99.30% P: 5.20, 99.42% ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.73-1.84 (m, 3 H), 1.91 (s, 2 H), 2.28 (s,3 H), 2.54-2.58 (m, 2 H), 2.66-2.69 (m, 1 H), 2.72 (s, 1 H), 2.79-2.88(m, 3 H), 2.92-2.99 (m, 2 H), 4.15 (m, 4 H), 4.16-5.38 (d, J = 1.51 Hz,2 H), 7.65 (d, J = 7.84 Hz, 1 H), 7.75 (s, 1 H), 7.80 (d, J = 7.91 Hz, 1H), 9.09 (s, 1 H). 168-I

(R)-4-methoxy-6-(4- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-2H-1,2,3- triazol-2- yl)nicotinonitrile446.2 E: 8.07, 99.40% G: 9.30, 99.10% XIV: 9.58, 99.00% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.90 (t, J = 10.39 Hz, 1 H), 2.21 (d, J = 2.93 Hz, 1H), 2.27 (s, 3 H), 2.79-2.94 (m, 3 H), 2.96-3.03 (m, 1 H), 3.77 (s, 2H), 4.09 (d, J = 8.07 Hz, 1 H), 4.13 (s, 3 H), 5.38 (d, J = 2.45 Hz,2H), 7.65 (d, J = 8.07 Hz, 1 H), 7.70 (s, 1 H), 7.78 (d, J = 7.83 Hz, 1H), 8.23 (s, 1 H), 8.83 (s, 1 H), (1 Exchangeable proton not observed).169-I

(R)-4-methyl-6-(4- methyl-5-((3-(4- methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2H-1,2,3- triazol-2-yl)nicotinonitrile 444.3 S: 1.29, 97.2% R: 1.05, 98.06% XIV: 6.83, 100%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (t, J = 10.4 Hz, 1 H), 2.13-2.23(m, 1 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 2.59 (s, 3 H), 2.78 (d, J =11.20 Hz, 2 H), 2.83-2.92 (m, 1 H), 2.96- 3.04 (m, 1 H), 3.63-3.77 (m, 2H), 4.06 (d, J = 7.80 Hz, 1 H), 5.36 (s, 2 H), 7.64 (d, J = 7.80 Hz, 1H), 7.78 (d, J = 7.80 Hz, 1 H), 8.03 (s, 1 H), 8.88 (s, 1 H), (1Exchangeable proton not observed). 170-I

4-methoxy-6-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2- oxopyrrolidin-1-yl)nicotinonitrile (Diastereomer-I) 476.3 S: 1.49, 100% R: 1.07, 99.06%XXXI: 4.36, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (d, J = 6.10Hz, 3 H), 1.74 (t, J = 9.80 Hz, 2 H), 2.31 (s, 3 H), 2.33-2.48 (m, 3 H),2.64-2.89 (m, 4H), 2.96 (br. s., 1 H), 3.77 (dd, J = 11.0, 5.40 Hz, 1H), 3.97 (s, 3 H), 4.12 (dd, J = 11.40, 7.70 Hz, 2 H), 5.31-5.50 (m, 2H), 7.67 (d, J = 8.10 Hz, 1 H), 7.82 (d, J = 8.10 Hz, 1 H), 8.18 (s, 1H), 8.66 (s, 1 H), (1 Exchangeable proton not observed). 171-I

6-(4-(((3R,4R)-4- hydroxy-3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-3-methyl-2- oxo-2,3-dihydro-1H-imidazol-1-yl)-4- methoxynicotinonitrile 490.2 P: 9.20, 99.40% Q: 5.03,98.10% XXVII: 5.46, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55-1.66(m, 1 H), 1.91-1.98 (m, 1 H), 2.07- 2.15 (m, 1 H), 2.25 (s, 4 H),2.74-2.81 (m, 1 H), 2.92-2.99 (m, 1 H), 3.01-3.08 (m, 1 H), 3.30 (s, 3H), 3.43 (d, J = 9.04 Hz, 2 H), 3.71-3.80 (m, 1 H), 4.01 (s, 3 H), 4.60(d, J = 5.52 Hz, 1 H), 5.36 (d, J = 8.53 Hz, 2 H), 7.27 (s, 1 H), 7.56(s, 1 H), 7.63-7.66 (m, 1 H), 8.27 (s, 1 H), 8.66 (s, 1 H). 172-I

6-(3-isopropyl-4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2-oxo-2,3-dihydro-1H-imidazol- 1-yl)-4- methoxynicotinonitrile 517.3 S: 1.88,98.00% R: 1.35, 98.45% XXX: 6.78, 96.70% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 1.05 (d, J = 6.40 Hz, 3 H), 1.51 (d, J = 6.80 Hz, 3 H), 1.50 (d, J =6.60 Hz, 3 H), 1.67-1.79 (m, 2 H), 2.24 (s, 3 H), 2.63 (br. s., 1 H),2.72-2.80 (m, 1 H), 2.85 (d, J = 10.00 Hz, 1 H), 2.88-2.99 (m, 1 H),3.45 (d, J = 14.20 Hz, 1 H), 4.02 (s, 3 H), 4.10 (d, J = 9.30 Hz, 1 H),4.36-4.48 (m, 1 H), 5.37 (s, 2 H), 7.26 (s, 1 H), 7.67 (d, J = 8.10 Hz,1 H), 7.83 (d, J = 7.80 Hz, 1 H), 8.28 (s, 1 H), 8.65 (s, 1 H), (1Exchangeable proton not observed). 173-I

3-methyl-4-(((3S,5R)- 3-methyl-5-(4-methyl- 1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1-(2-methylpyrimidin-4-yl)- 1,3-dihydro-2H- imidazol-2-one 449.3 S: 1.29,98.42% R: 0.78, 97.30% VI: 12.32, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 1.04 (d, J = 6.10 Hz, 3 H), 1.84-1.64 (m, 2 H), 2.26 (s, 3 H), 2.56(s, 3 H), 2.83 (t, J = 8.40 Hz, 2 H), 2.87-2.99 (m, 1 H), 3.29 (s, 3 H),3.40 (s, 2 H), 4.12 (d, J = 7.80 Hz, 1 H), 5.38 (s, 2 H), 7.27 (s, 1 H),7.67 (d, J = 8.30 Hz, 1 H), 7.82 (d, J = 8.10 Hz, 1 H), 8.18 (d, J =5.60 Hz, 1 H), 8.66(d, J = 5.60 Hz, 1 H), (1 Exchangeable proton notobserved). 174-I

3-(5-(((3S,5R)-3- methyl-5-(4-methyl-1- oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-[2,4′- bipyridin]-2′- yl)oxazolidin-2-one500.3 S: 1.37, 98.95% R: 0.66, 98.40% XVII: 11.04, 100% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.04 (br. s., 3 H), 1.78 (d, J = 13.00 Hz, 2 H),1.92 (s, 1 H), 2.25 (s, 3 H), 2.80 (br. s., 2 H), 2.99 (br. s., 1 H),3.61 (br. s., 2 H), 4.07-4.30 (m, 3 H), 4.42-4.54 (m, 2 H), 5.29-5.47(m, 2 H), 7.47- 7.56 (m, 1 H), 7.59-7.75 (m, 1 H), 7.75-7.88 (m, 2 H),7.94 (d, J = 8.10 Hz, 1 H), 8.28 (s, 1 H), 8.60 (s, 1 H), (1Exchangeable proton not observed). 175-I

6-(4-((3,3-dimethyl-5- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-5-methyl- 2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile (Enantiomer-I) 472.3 S: 1.96, 98.70% R: 1.41,98.60% VIII: 3.60 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (s, 3 H),1.20-1.41 (m, 3 H), 1.82 (t, J = 9.00 Hz, 1 H), 1.93 (d, J = 9.80 Hz, 1H), 2.06 (d, J = 13.20 Hz, 1 H), 2.26 (s, 3 H), 2.45 (s, 3 H), 2.54-2.64 (m, 3 H), 2.79 (d, J = 10.00 Hz, 1 H), 3.68 (s, 2 H), 4.38 (d, J =9.50 Hz, 1 H), 5.37 (s, 2 H), 7.66 (d, J = 8.60 Hz, 1 H), 7.79 (d, J =8.10 Hz, 1 H), 8.03 (s, 1 H), 8.88 (s, 1 H), (1 Exchangeable proton notobserved). 176-I

4-methyl-6-(5-methyl- 4-(((3S,5R)-3-methyl- 5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-1,2,3- triazol-1-yl)nicotinonitrile 458.3 S: 1.69, 96.05% R: 1.09, 96.40% VIII: 10.08100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J = 6.10 Hz, 3 H),1.73-1.90 (m, 2 H), 2.21-2.31 (m, 3 H), 2.59 (s, 3 H), 2.64 (s, 3 H),2.75-2.87 (m, 2 H), 2.95 (br. s., 1 H), 3.61-3.74 (m, 2 H), 4.15 (d, J =8.10 Hz, 1 H), 5.31-5.43 (m, 2 H), 7.66 (d, J = 8.10 Hz, 1 H), 7.80 (d,J = 7.80 Hz, 1 H), 8.17 (s, 1 H), 9.01 (s, 1 H), (1 Exchangeable protonnot observed). 177-I

(R)-4-methyl-5-(4-((1- (1-methyl-1H- pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4- yl)methyl)morpholin- 2-yl)isobenzofuran- 1(3H)-one444.2 A: 1.41, 98.80% B: 0.95, 98.40% ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.30 (s, 3 H), 3.15-3.20 (m, 2 H), 3.50-3.90 (m, 2 H), 3.90-3.40 (m, 5H), 4.40 (br. s., 2 H), 5.10 (br. s., 1 H), 5.40-5.50 (m, 2 H), 7.10 (m,1 H), 7.52 (d, J = 5.20 Hz, 1 H), 7.64-7.68 (m, 2 H), 7.75 (d, J = 8.00Hz, 1 H), 8.0 (s, 1 H), 8.35 (d, J = 8.00 Hz, 1 H), 8.90 (s, 1 H). 178-I

4-methyl-5-((2R,6S)-6- methyl-4-((1-(p-tolyl)- 1H-imidazol-4-yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 417.3 A: 1.35, 97.80%B: 0.79, 99.10% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J = 6.02 Hz, 3H), 1.72-1.83 (m, 2 H) 2.27 (s, 3 H) 2.34 (s, 3 H), 2.85 (d, J = 11.55Hz, 2 H), 2.90-3.00 (m, 1 H), 3.45 (s, 2 H), 4.15 (dd, J = 10.04, 2.01Hz, 1 H), 5.38 (s, 2 H), 7.30 (d, J = 8.53 Hz, 2 H), 7.49-7.56 (m, 3 H),7.65 (d, J = 7.53 Hz, 1 H), 7.82 (s, 1 H), 8.06-8.07 (m, 1 H), (1Exchangeable proton not observed). 179-I

4-methyl-5-((2R,6S)-6- methyl-4-((1-(3- methylpyridin-4-yl)-1H-imidazol-4- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 418.2A: 0.97, 96.90% B: 0.53, 94.90% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d,J = 6.02 Hz, 3 H), 1.72-1.83 (m, 2 H), 2.24-2.31 (m, 6 H), 2.85 (d, J =11.55 Hz, 2 H), 2.90-3.00 (m, 1 H), 3.45 (s, 2 H), 4.15 (dd, J = 10.04,2.01 Hz, 1 H), 5.38 (s, 2 H), 7.30 (d, J = 8.53 Hz, 2 H), 7.65 (d, J =7.53 Hz, 1 H), 7.82 (d, J = 7.53 Hz, 1 H), 7.92 (s, 1 H), 7.52 (d, J =5.20 Hz, 1 H), 8.61 (s, 1 H), (1 Exchangeable proton not observed).180-I

4-methyl-5-((2R,6S)-6- methyl-4-((1-(6- methylpyridin-3-yl)-1H-imidazol-4- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 418.2A: 1.00, 98.60% B: 0.59, 95.40% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d,J = 6.02 Hz, 3 H), 1.69-1.85 (m, 2 H), 2.23 (s, 3 H), 2.50 (s, 3 H),2.85 (br. s., 2 H), 2.95 (d, J = 3.51 Hz, 1 H), 3.43-3.50 (m, 2 H), 4.15(d, J = 9.54 Hz, 1 H), 5.38 (s, 2 H), 7.39 (d, J = 8.53 Hz, 1 H), 7.65(d, J = 8.03 Hz, 2 H), 7.80 (d, J = 8.03 Hz, 1 H), 7.98 (s, 1 H),8.12-8.32 (m, 1 H), 8.77 (d, J = 2.51 Hz, 1 H), (1 Exchangeable protonnot observed). 181-I

5-((2R,6S)-4-((1-(2,6- dimethylpyridin-4-yl)- 1H-imidazol-4-yl)methyl)-6- methylpiperazin-2-yl)- 4- methylisobenzofuran- 1(3H)-one.432.3 A: 0.99, 99.50% B: 0.79, 94.90% ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.97-1.07 (m, 3 H), 1.74-1.82 (m, 2 H), 2.27 (s, 3 H), 2.46 (s, 6 H),2.83 (d, J = 10.80 Hz, 2 H), 2.96 (br. s., 1 H), 3.39-3.41 (m, 2 H),4.15 (d, J = 8.20 Hz, 1 H), 5.38 (br. s., 2 H), 7.44 (s, 1 H), 7.64-7.66 (m, 2 H), 7.80 (d, J = 8.00 Hz, 1 H), 7.95- 7.97 (m, 1 H), 8.80 (s,1 H), (1 Exchangeable proton not observed). 182-I

5-((2R,6S)-4-((1-(2,2- difluorobenzo[d][1,3]di- oxol-5-yl)-1H-imidazol-4-yl)methyl)- 6-methylpiperazin-2- yl)-4- methylisobenzofuran-1(3H)-one 483.3 A: 1.48, 97.10% B: 0.92, 97.80% ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.96-1.06 (m, 3 H), 1.80 (br. s., 2 H), 2.27 (s., 3 H),2.80-2.90 (m, 3 H), 3.40 (br. s., 2 H), 4.10 (br. s., 1 H), 5.32-5.45(m, 2 H), 7.50-7.60 (m, 3 H), 7.70-7.75 (m, 2 H), 7.85-7.90 (m, 2 H), (1Exchangeable proton not observed). 183-I

(R)-4-methyl-6-(2-((3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-5- yl)nicotinonitrile 441.2 A:0.93, 97.97% B: 1.12, 100% XVIII: 23.32, 95.58% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.03 (t, J = 10.40 Hz, 1 H), 2.27 (s, 3 H), 2.32 (d, J =3.4 Hz, 1 H), 2.59 (s, 3 H), 2.81-3.05 (m, 4 H), 3.84 (s, 2 H), 4.10 (d,J = 8.60 Hz, 1 H), 5.37 (s, 2 H), 7.64 (d, J = 7.80 Hz, 1 H), 7.79 (d, J= 7.80 Hz, 1 H), 8.31 (s, 1 H), 9.06 (s, 1 H), 9.44 (s, 2 H), (1Exchangeable proton not observed). 184-I

(R)-2,4-dimethyl-6-(4- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-2H-1,2,3- triazol-2- yl)nicotinonitrile444.2 A: 1.04, 100% B: 1.27, 99.69% XIV: 10.30 98.57% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.84-1.97 (m, 1 H), 2.16-2.24 (m, 1 H), 2.26 (s, 3H), 2.59 (s, 3 H), 2.69-2.73 (m, 3 H), 2.82 (d, J = 10.0 Hz, 2 H),2.88-2.95 (m, 1 H), 2.97-3.05 (m, 1 H), 3.76 (s, 2 H), 4.10 (d, J = 9.30Hz, 1 H), 5.31-5.48 (m, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.77 (d, J =8.10 Hz, 1 H), 7.93 (s, 1 H), 8.18 (s, 1 H), (1 Exchangeable proton notobserved). 185-I

(R)-3-(2-(4-((3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)pyridin-4-yl)oxazolidin-2-one 475.1 S: 1.35, 100% R: 1.11, 100% XIV: 15.72, 98.00%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79 (t, J = 10.15 Hz, 1 H),2.07-2.15 (m, 1 H), 2.25 (s, 3 H), 2.77-3.01 (m, 3 H), 3.17 (d, J = 5.14Hz, 1 H), 3.46-3.56 (m, 2 H), 4.04-4.17 (m, 3 H), 4.47-4.54 (m, 2 H),5.36 (s, 2 H), 7.42 (dd, J = 5.87, 2.20 Hz, 1 H), 7.63 (d, J = 8.07 Hz,1 H), 7.72-7.79 (m, 2 H), 8.16 (d, J = 2.20 Hz, 1 H), 8.35 (d, J = 5.87Hz, 1 H), 8.47 (s, 1 H), (1 Exchangeable proton not observed). 186-I

(R)-2,4-dimethyl-6-(4- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-1,2,3- triazol-1- yl)nicotinonitrile444.2 C: 6.15, 98.53% G: 6.95, 99.21% V: 11.71, 99.21% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.87 (t, J = 10.39 Hz, 1 H), 2.12-2.22 (m, 1 H),2.26 (s, 3 H), 2.62 (s, 3 H), 2.69-2.75 (m, 3 H), 2.78-2.92 (m, 3 H),2.95-3.02 (m, 1 H), 3.74 (s, 2 H), 4.06 (d, J = 7.58 Hz, 1 H), 5.38 (s,2 H), 7.64 (d, J = 8.07 Hz, 1 H), 7.76 (d, J = 8.07 Hz, 1 H), 8.10 (s, 1H), 8.74 (s, 1 H), (1 Exchangeable proton not observed). 187-I

(R)-4-methoxy-2- methyl-6-(4-((3-(4- methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-1,2,3- triazol-1-yl)nicotinonitrile 460.3 R: 1.06, 100% S: 1.27, 99.47% V: 10.37, 98.87%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87-1.98 (m, 1 H), 2.14-2.24 (m, 1H), 2.27 (s, 3 H), 2.64-2.69 (m, 3 H), 2.85 (t, J = 9.50 Hz, 2 H), 2.92(d, J = 10.00 Hz, 1 H), 2.97-3.05 (m, 1 H), 3.76 (s, 2 H), 4.04-4.19 (m,4 H), 5.31-5.46 (m, 2 H), 7.65 (d, J = 7.80 Hz, 1 H), 7.73 (s, 1 H),7.76 (d, J = 7.80 Hz, 1 H), 8.75 (s, 1 H), (1 Exchangeable proton notobserved). 188-I

(R)-4-methoxy-2- methyl-6-(4-((3-(4- methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2H-1,2,3- triazol-2-yl)nicotinonitrile 460.3 R: 1.02, 100% S: 1.20, 98.54% V: 8.18, 99.14%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (t, J = 10.30 Hz, 1 H),2.13-2.25 (m, 1 H), 2.26 (s, 3 H), 2.64 (s, 3 H), 2.82 (d, J = 11.20 Hz,2 H), 2.90 (t, J = 11.20 Hz, 1 H), 3.00 (d, J = 12.00 Hz, 1 H), 3.76 (s,2 H), 4.03-4.17 (m, 4 H), 5.27- 5.46 (m, 2 H), 7.55 (s, 1 H), 7.65 (d, J= 8.10 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1 H), 8.19 (s, 1 H), (1Exchangeable proton not observed). 189-I

(R)-2-methoxy-4- methyl-6-(4-((3-(4- methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-1,2,3- triazol-1-yl)nicotinonitrile 460.3 R: 1.13, 100% S: 1.35, 100% VI: 14.78, 98.24%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87-1.98 (m, 1 H), 2.14-2.24 (m, 1H), 2.28 (s, 3 H), 2.59 (s, 3 H), 2.85 (t, J = 9.50 Hz, 2 H), 2.91 (br.s., 2 H), 3.78 (br. s., 2 H), 4.11 (s, 4 H), 5.39 (d, J = 3.70 Hz, 2 H),7.71 (br. s., 1 H), 7.80-7.74 (m, 1 H), 7.83 (s, 1 H), 8.85 (s, 1 H), (1Exchangeable proton not observed). 190-I

6-(4-((3,3-dimethyl-5- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-2H-1,2,3- triazol-2-yl)-4-methoxynicotinonitrile (Enantiomer-I) 474.3 R: 1.10, 97.63% S: 1.53,96.84% XVIII: 17.70, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (s, 3H), 1.32 (s, 3 H), 1.85 (t, J = 10.40 Hz, 1 H), 1.93 (d, J = 10.50 Hz, 1H), 2.04 (br. s., 1 H), 2.29 (s, 3 H), 2.57 (d, J = 10.80 Hz, 1 H), 2.88(d, J = 10.00 Hz, 1 H), 3.65-3.88 (m, 2 H), 4.13 (s, 3 H), 4.42 (d, J =9.00 Hz, 1 H), 5.32-5.47 (m, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.70 (s,1 H), 7.80 (d, J = 8.10 Hz, 1 H), 8.21 (s, 1 H), 8.83 (s, 1 H). 191-I

4-methyl-6-(5- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1,3,4- oxadiazol-2-yl)nicotinonitrile 445.2 A: 0.95, 100% B: 1.26, 100% XIV: 8.77, 100% ¹HNMR (400 MHz, DMSO-d₆) δ 1.03 (d, J = 6.40 Hz, 3 H), 1.87-2.03 (m, 2 H),2.30 (s, 3 H), 2.63 (s, 3 H), 2.78-2.93 (m, 2 H), 2.99 (br. s., 1 H),4.00 (s, 2 H), 4.19 (d, J = 7.60 Hz, 1 H), 5.40 (s, 2 H), 7.66 (d, J =8.10 Hz, 1 H), 7.79 (d, J = 8.10 Hz, 1 H), 8.32 (s, 1 H), 9.11 (s, 1 H),(1 Exchangeable proton not observed). 192-I

4-methoxy-6-(4-(2- ((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)ethyl)-1H-pyrazol-1-yl)nicotinonitrile 433.3 R: 0.54, 100% S: 1.26, 94.95% XV: 6.26, 100% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (d, J = 6.10 Hz, 3 H), 1.24 (s, 1H), 1.65-1.82 (m, 2 H), 2.27-2.34 (m, 3 H), 2.56 (d, J = 7.10 Hz, 1 H),2.59-2.65 (m, 3 H), 2.65-2.74 (m, 2 H), 2.88 (d, J = 10.30 Hz, 2 H),2.96 (br. s., 1 H), 4.16 (d, J = 9.80 Hz, 1 H), 5.32-5.47 (m, 2 H),7.62-7.72 (m, 2 H), 7.78-7.90 (m, 2 H), 8.52 (s, 1 H), 8.73 (d, J = 5.60Hz, 1 H), (1 Exchangeable proton not observed). 193-I

6-(5-(((3R,4R)-4- hydroxy-3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)isoxazol-3- yl)-4- methylnicotinonitrile445.3 R: 1.17, 100% S: 1.58, 100% XVIII: 5.84, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.59-1.70 (m, 1 H), 1.94 (d, J = 9.50 Hz, 1 H), 2.16-2.41(m, 5 H), 2.59 (s, 3 H), 2.79 (d, J = 11.20 Hz, 1 H), 2.95 (d, J = 10.30Hz, 1 H), 3.09 (t, J = 10.40 Hz, 1 H), 3.64-3.77 (m, 1 H), 3.86 (br. s.,2 H), 4.61 (d, J = 5.40 Hz, 1 H), 5.30-5.49 (m, 2 H), 6.99 (s, 1 H),7.54 (d, J = 8.10 Hz, 1 H), 7.64 (d, J = 7.80 Hz, 1 H), 8.15 (s, 1 H),9.05 (s, 1 H). 194-I

5-((2R,6S)-4-((1-(4- methoxy-1,3,5-triazin- 2-yl)-1H-pyrazol-4-yl)methyl)-6- methylpiperazin-2-yl)- 4- methylisobenzofuran- 1(3H)-one436.2 R: 0.76, 100% S: 1.09, 100% VIII: 9.06, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.93-1.11 (m, 3 H), 1.73 (td, J = 10.6, 4.3 Hz, 2 H),2.26 (s, 3 H), 2.80 (d, J = 10.80 Hz, 2 H), 2.94- 3.02 (m, 1 H),3.45-3.58 (m, 2 H), 3.98-4.11 (m, 3 H), 4.13-4.21 (m, 1 H), 5.31-5.47(m, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.79 (d, J = 8.10 Hz, 1 H),7.95-7.86 (m, 1 H), 8.57 (s, 1 H), 8.96 (s, 1 H), (1 Exchangeable protonnot observed). 195-I

6-(4-(((3R,5R)-3- (hydroxymethyl)-4- methyl-5-(4-methyl-1- oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4-methylnicotinonitrile 473.3 R: 1.10, 96.00% S: 1.47, 95.73% XV: 4.2Z,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.88 (br. s., 1 H), 1.93-2.08(m, 4 H), 2.27 (br. s., 3 H), 2.36 (d, J = 10.00 Hz, 1 H), 2.58 (s, 3H), 2.72 (d, J = 11.70 Hz, 1 H), 3.09 (d, J = 11.00 Hz, 1 H), 3.18 (d, J= 4.60 Hz, 1 H), 3.43-3.54 (m, 2 H), 3.58-3.73 (m, 2 H), 4.55 (br. s., 1H), 5.30- 5.47 (m, 2 H), 7.59-7.73 (m, 2 H), 7.84 (s, 1 H), 7.99 (s, 1H), 8.52 (s, 1 H), 8.83 (s, 1 H). 196-I

6-(4-(((3S,5R)-3- methyl-5-(4-methyl-1- oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4-(trifluoromethyl)nicotino- nitrile 497.3 R: 1.91, 100% S: 2.07, 100%XXVIII: 4.19, 96.40% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J =6.10 Hz, 3 H), 1.64-1.81 (m, 2 H), 2.27 (s, 3 H), 2.81 (d, J = 9.80 Hz,2 H), 2.97 (br. s., 1 H), 3.55 (s, 2 H), 4.17 (d, J = 9.00 Hz, 1 H),5.28-5.46 (m, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.79 (d, J = 7.80 Hz, 1H), 7.96 (s, 1 H), 8.24 (s, 1 H), 8.61 (s, 1 H), 9.23 (s, 1 H), (1Exchangeable proton not observed). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm−63.47. 197-I

4-methyl-6-(4-((3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H-pyrazol- 1-yl)nicotinonitrile(Enantiomer-I) 428.1 S: 1.98, 98.50% R: 1.40, 94.37% V: 11.03, 97.37% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (br. s., 1 H), 1.75 (br. s., 3 H),2.04 (br. s., 2 H), 2.24 (s, 3 H), 2.54-2.62 (m, 3 H), 2.73-3.00 (m, 2H), 3.04-3.24 (m, 1 H), 3.53 (br. s., 2 H), 5.36 (s, 2 H), 7.49 (d, J =8.07 Hz, 1 H), 7.63 (d, J = 7.09 Hz, 1 H), 7.87 (br. s., 1 H), 7.99 (s,1 H), 8.54 (br. s., 1 H), 8.83 (s, 1 H). 198-I

(R)-2-(4-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)isonicotinonitrile 415.1S: 1.20, 100% R: 0.87, 100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.83 (t, J =10.90 Hz, 1 H), 2.14 (t, J = 9.80 Hz, 1 H), 2.26 (s, 3 H), 2.81 (d, J =8.10 Hz, 2 H), 2.94- 2.86 (m, 1 H), 3.05-2.97 (m, 1 H), 3.59-3.45 (m, 2H), 4.10 (d, J = 9.30 Hz, 1 H), 5.45-5.30 (m, 2 H), 7.64 (d, J = 8.10Hz, 1 H), 7.80-7.70 (m, 2 H), 7.83 (s, 1 H), 8.22 (s, 1 H), 8.51 (s, 1H), 8.68 (d, J = 5.10 Hz, 1H), (1 Exchangeable proton not observed).199-IV

6-(4-((3-hydroxy-5-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methylnicotinonitrile(Enantiomer-IV) 459.3 S: 1.42, 97.51% R: 1.01, 96.70% XVIII: 19.33, 100%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70 (br. s., 2 H), 2.25 (s, 4 H),2.58 (s, 3 H), 2.77 (br. s., 2 H), 3.57 (br. s., 3 H), 3.86 (br. s., 1H), 4.63 (br. s., 1 H), 5.36 (s, 2 H), 7.67-7.52 (m, 2 H), 7.89 (s, 1H), 7.99 (s, 1 H), 8.57 (s, 1 H), 8.83 (s, 1 H), (1 Exchangeable protonnot observed). 200-II

6-(4-((3-methoxy-5-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methylnicotinonitrile(Enantiomer-II) 458.2 S: 1.66, 97.24% R: 1.13, 97.40% XVIII: 18.01, 100%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-1.30 (m, 1 H), 1.84 (t, J =10.60 Hz, 1 H), 1.95 (t, J = 10.80 Hz, 1 H), 2.14 (s, 1 H), 2.24 (s, 3H), 2.58 (s, 3 H), 2.81 (d, J = 11.70 Hz, 1 H), 3.16 (d, J = 11.20 Hz, 1H), 3.24 (d, J = 6.10 Hz, 1 H), 3.29 (s, 3 H), 3.48 (s, 1 H), 3.69-3.55(m, 2 H), 5.36 (s, 2 H), 7.48 (d, J = 7.80 Hz, 1 H), 7.62 (d, J = 8.30Hz, 1 H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8.54 (s, 1 H), 8.83 (s, 1 H).201-I

(R)-5-(4-((2-(3,5- dimethyl-4H-1,2,4- triazol-4-yl)pyrimidin-5-yl)methyl)piperazin- 2-yl)-4- methylisobenzofuran- 1(3H)-one 420.2 S:0.88, 97.02% R: 0.70, 96.77% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.95-1.83(m, 1 H), 2.23-2.08 (m, 2 H), 2.32- 2.24 (m, 6 H), 2.70 (s, 3 H), 2.80(t, J = 10.90 Hz, 2 H), 2.92 (t, J = 10.30 Hz, 1 H), 3.07-2.98 (m, 1 H),3.73-3.54 (m, 2 H), 4.11 (d, J = 8.30 Hz, 1 H), 5.48-5.29 (m, 2 H), 7.66(d, J = 7.80 Hz, 1 H), 7.79 (d, J = 7.80 Hz, 1 H), 8.86 (s, 2 H). 202-I

3-methyl-2-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol-1-yl)isonicotinonitrile 443.3 S: 1.41, 99.79% R: 0.94, 99.70% XVIII:8.45, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (t, J = 7.20 Hz, 3H), 2.36 (s, 3 H), 2.68 (s, 3 H), 2.99-2.87 (m, 2 H), 3.15 (br. s., 2H), 3.64 (br. s., 1 H), 3.76 (br. s., 1 H), 3.84 (s, 1 H), 4.75 (br. s.,1 H), 5.60-5.37 (m, 2 H), 7.87-7.73 (m, 3 H), 7.90 (d, J = 4.90 Hz, 1H), 8.32 (br. s., 1 H), 8.42 (br. s., 1 H), 8.59 (d, J = 4.60 Hz, 1 H).203-I

6-(4-((3-fluoro-5-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H-1,2,3- triazol-1-yl)-4-methylnicotinonitrile (Enantiomer-I) 447.2 S: 1.66, 100% R: 1.17, 100%XXVIII: 6.53, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79-1.65 (m, 1H), 2.24-2.03 (m, 3 H), 2.26 (s, 3 H), 2.67-2.60 (m, 3 H), 2.86 (d, J =10.80 Hz, 1 H), 3.21 (t, J = 10.80 Hz, 1 H), 3.31 (d, J = 3.90 Hz, 1 H),3.96-3.79 (m, 2 H), 4.95-4.68 (m, 1 H), 5.38 (s, 2 H), 7.54 (d, J = 8.10Hz, 1 H), 7.65 (d, J = 8.10 Hz, 1 H), 9.00 (s, 1 H), 8.85 (s, 1 H), 8.30(s, 1 H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ ppm −178.31. 204-I

6-(4-((3-(1- hydroxyethyl)-5-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methoxynicotinonitrile(Enantiomer-I) 489.3 S: 1.38, 99.33% R: 1.05, 97.87% XXVIII: 5.73,95.11% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (d, J = 6.0 Hz, 3 H),1.77 (br. s., 2 H), 2.27 (s, 3 H), 2.74 (s, 3 H), 3.01 (br. s., 1 H),3.54 (br. s., 3 H), 4.11 (s, 3 H), 4.15 (br. s., 1 H), 4.54 (br. s., 1H), 5.39 (s, 2 H), 7.61 (s, 1 H), 7.66 (d, J = 6.40 Hz, 1 H), 7.80 (d, J= 8.30 Hz, 1 H), 7.87 (s, 1 H), 8.53 (br. s., 1 H), 8.75 (s, 1 H). 205-I

6-(4-((3- (difluoromethyl)-5-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methylnicotinonitrile(Enantiomer-I) 479.2 S: 1.80, 94.40% R: 1.23, 94.62% X: 4.29, 89.07% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.77 (br. s., 1 H), 2.01 (br. s., 1 H),2.14-2.08 (m, 1 H), 2.27 (s, 3 H), 2.58 (s, 3 H), 2.84 (br. s., 2 H),2.94 (br. s., 1 H), 3.62 (br. s., 2 H), 4.24 (br. s., 1 H), 5.49-5.30(m, 2 H), 5.96 (br. s., 1 H), 7.67 (d, J = 7.60 Hz, 1 H), 7.77 (d, J =8.10 Hz, 1 H), 7.88 (br. s., 1 H), 8.00 (s, 1 H), 8.57 (br. s., 1 H),8.84 (s, 1 H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ ppm −126.20, −126.07. 206-I

4-methyl-5-((2R,6S)-6- methyl-4-((1-(5- methylpyrazin-2-yl)-1H-pyrazol-4- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 419.3R: 0.63, 94.20% S: 1.40, 95.10% VIII: 5.80, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.03 (d, J = 6.10 Hz, 3 H), 1.73 (br. s., 2 H), 2.31-2.18 (m, 3 H), 2.56-2.52 (m, 4 H), 2.81 (d, J = 10.30 Hz, 2 H), 2.98(br. s., 1 H), 3.53 (s, 2 H), 4.16 (br. s., 1 H), 5.37 (d, J = 2.00 Hz,2 H), 7.65 (d, J = 7.80 Hz, 1 H), 7.88-7.74 (m, 2 H), 8.40 (s, 1 H),8.45 (s, 1 H), 9.05 (d, J = 1.50 Hz, 1 H). 207-I

5-((2R,6S)-4-((1-(6- methoxypyrimidin-4- yl)-1H-pyrazol-4- yl)methyl)-6-methylpiperazin-2-yl)- 4- methylisobenzofuran- 1(3H)-one 435.2 S: 1.34,99.14% R: 0.73, 100% XXV: 13.93, 98.14% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 1.02 (d, J = 6.10 Hz, 3 H), 1.80-1.61 (m, 2 H), 2.26 (s, 3 H), 2.79(d, J = 10.30 Hz, 2 H), 2.96 (br. s., 1 H), 3.18 (d, J = 5.40 Hz, 1 H),3.51 (s, 2 H), 3.99 (s, 3 H), 4.15 (d, J = 8.60 Hz, 1 H), 5.47-5.29 (m,2 H), 7.16 (d, J = 1.00 Hz, 1 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.79 (d, J= 8.10 Hz, 1 H), 7.88- 7.81 (m, 1 H), 8.49 (s, 1 H), 8.71 (d, J = 1.00Hz, 1 H). 208-I

5-((2R,6S)-4-((1-(2- methoxypyrimidin-5- yl)-1H-pyrazol-4- yl)methyl)-6-methylpiperazin-2-yl)- 4- methylisobenzofuran- 1(3H)-one 435.3 S: 1.07,95.74% R: 0.55, 98.67% XIV: 5.56, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δppm 1.03 (d, J = 5.60 Hz, 3 H), 1.73 (d, J = 10.30 Hz, 2 H), 2.27 (s, 3H), 2.82 (d, J = 10.30 Hz, 2 H), 2.98 (br. s., 1 H), 3.48 (s, 2 H), 3.97(s, 3 H), 4.18 (br. s., 1 H), 5.47-5.28 (m, 2 H), 7.66 (d, J = 7.80 Hz,1 H), 7.72 (s, 1 H), 7.80 (d, J = 8.10 Hz, 1 H), 8.42 (s, 1 H), 9.05 (s,2 H), (1 Exchangeable proton not observed). 209-I

4-methyl-5-((2R,6S)-6- methyl-4-((1-(2- methylpyrimidin-5-yl)-1H-pyrazol-4- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 419.2S: 0.98, 93.79% R: 0.50, 98.28% XXVI: 9.79, 100% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.04 (d, J = 6.10 Hz, 3 H), 1.72 (br. s., 2 H), 2.33-2.14 (m, 3 H), 2.70-2.60 (m, 3 H), 2.82 (d, J = 8.60 Hz, 2H), 2.98 (br.s., 1 H), 3.49(s, 2H), 4.16 (br. s., 1 H), 5.45-5.30 (m, 2 H), 7.66 (d,J = 8.10 Hz, 1 H), 7.76 (s, 1 H), 7.80 (d, J = 8.10 Hz, 1 H), 8.53 (s, 1H), 9.22-9.09 (m, 2 H), (1 Exchangeable proton not observed). 210-I

4-methyl-6-(3- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)isoxazol-5-yl)nicotinonitrile 444.2 R: 1.50, 94.28% S: 1.13, 95.39% ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.04 (d, J = 6.10 Hz, 3 H), 1.94-1.80 (m, 2 H), 2.27(s, 3 H), 2.64-2.54 (m, 4 H), 2.82 (d, J = 10.30 Hz, 2 H), 3.00 (br. s.,1 H), 3.72 (s, 2 H), 4.19 (d, J = 8.10 Hz, 1 H), 5.38 (s, 2 H), 7.23 (s,1 H), 7.66 (d, J = 8.10 Hz, 1 H), 7.80 (d, J = 7.80 Hz, 1 H), 8.14 (s,1H), 9.04 (s, 1 H). 211-I

6-(4-((3-hydroxy-4-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)pyrrolidin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methylnicotinonitrile(Diastereomer-I: Enantiomer-I) 430.2 R: 0.99, 100% S: 1.25, 100% XVIII:16.83, 99.40% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.26 (s, 3 H), 2.58 (s,3 H), 2.84-3.03 (m, 2 H), 3.19 (dd, J = 10.10, 5.70 Hz, 1 H), 3.51-3.63(m, 1 H), 3.70 (s, 2 H), 4.38-4.48 (m, 1 H), 4.51 (d, J = 4.90 Hz, 1 H),5.36 (s, 2 H), 7.54 (d, J = 7.80 Hz, 1 H), 7.59 (d, J = 8.10 Hz, 1 H),7.91 (s, 1 H), 7.99 (s, 1 H), 8.59 (s, 1 H), 8.85 (s, 1 H). (1Exchangeable proton not observed). 212-II

6-(4-((3-fluoro-4-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)pyrrolidin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methylnicotinonitrile(Diastereomer-I: Enantiomer-II) 432.2 R: 1.12, 94.07% S: 1.80, 93.34%VIII: 4.92, 99.73% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H),2.59 (s, 3 H), 2.93-3.02 (m, 1 H), 3.05 (br. s., 1 H), 3.24-3.29 (m, 1H), 3.39 (d, J = 6.10 Hz, 1 H), 3.69 (s, 2 H), 3.74 (d, J = 5.60 Hz, 1H), 3.78-3.88 (m, 1 H), 5.40 (s, 2 H), 7.53 (d, J = 8.30 Hz, 1 H), 7.69(d, J = 7.80 Hz, 1 H), 7.92 (s, 1 H), 8.01 (s, 1 H), 8.60 (s, 1 H), 8.86(s, 1 H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −164.03. 213-I

6-(4-((3-(2- hydroxypropan-2-yl)- 5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4-methylnicotinonitrile (Enantiomer-I) 487.3 R: 1.18, 93.00% S: 1.61,93.00% XXV: 6.47, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (d, J =3.90 Hz, 6 H), 1.71 (t, J = 10.40 Hz, 1 H), 1.82 (t, J = 10.50 Hz, 1 H),2.26 (s, 3 H), 2.58 (s, 3 H), 2.73-2.85 (m, 2 H), 2.92 (d, J = 10.00 Hz,1 H), 3.51 (d, J = 13.90 Hz, 1 H), 3.59 (d, J = 13.70 Hz, 1 H), 4.15 (d,J = 7.60 Hz, 1 H), 4.40 (br. s., 1 H), 5.37 (s, 2 H), 7.66 (d, J = 7.80Hz, 1 H), 7.82 (d, J = 7.80 Hz, 1 H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8.53(s, 1 H), 8.83 (s, 1 H). (1 Exchangeable proton not observed). 214-I

4-methyl-6-(5- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)isoxazol-3-yl)nicotinonitrile 444.2 R: 1.16, 97.73% S: 1.56, 97.61% XVIII: 5.63,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J = 6.10 Hz, 3 H), 1.86(dt, J = 13.60, 10.5 Hz, 2 H), 2.28 (s, 3 H), 2.55-2.65 (m, 4 H), 2.83(d, J = 10.80 Hz, 2 H), 2.93-3.04 (m, 1 H), 3.86 (s, 2 H), 4.17 (d, J =8.10 Hz, 1 H), 5.39 (s, 2 H), 6.98 (s, 1 H), 7.65 (d, J = 7.80 Hz, 1 H),7.73-7.83 (m, 1 H), 8.15 (s, 1 H), 9.05 (s, 1 H). 215-I

(R)-4-methyl-5-(4-((2- (4-methyl-1H- imidazol-1- yl)pyrimidin-5-yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 416.20 A: 1.07,99.60% B: 1.32, 98.32% XVIII: 16.98, 98.00% ee ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.87-1.96 (m, 1 H), 2.12-2.17 (m, 1 H), 2.24 (s, 3 H), 2.75-2.85(m, 2 H), 2.94 (d, J = 12.96 Hz, 1 H), 3.02 (d, J = 11.98 Hz, 1 H),3.54-3.65 (m, 2 H), 4.12 (d, J = 8.80 Hz, 1 H), 5.31-5.43 (m, 2 H),7.62-7.69 (m, 2 H), 7.77 (d, J = 7.83 Hz, 1 H), 8.44 (d, J = 1.22 Hz, 1H), 8.75 (s, 2 H), (1 Exchangeable proton not observed). 216-I

(R)-1-(5-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-2- yl)-1H-imidazole-4-carbonitrile 405.20 E: 7.08, 97.55% G: 8.03, 98.45% XIV: 7.18, 98.01% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87-1.96 (m, 1 H), 2.12-2.17 (m, 1 H),2.18 (s, 3 H), 2.24 (s, 3 H), 2.75-2.85 (m, 2 H), 2.94 (d, J = 12.96 Hz,1 H), 3.02 (d, J = 11.98 Hz, 1 H), 3.54- 3.65 (m, 2 H), 4.12 (d, J =8.80 Hz, 1 H), 5.31- 5.43 (m, 2 H), 7.62-7.69 (m, 2 H), 7.77 (d, J =7.83 Hz, 1 H), 8.44 (d, J = 1.22 Hz, 1 H), 8.75 (s, 2 H), (1Exchangeable proton not observed). 217-I

(R)-1-(5-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-2- yl)-1H-1,2,4-triazole-3-carbonitrile 417.5 S: 1.14, 98.53% R: 1.34, 99.21% XVIII: 24.93, 100% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92 (t, J = 10.64 Hz, 1 H), 2.15-2.22(m, 1 H), 2.25 (s, 3 H), 2.80 (t, J = 9.05 Hz, 2 H), 2.87-2.96 (m, 1 H),2.96-3.05 (m, 1 H), 3.58-3.74 (m, 2 H), 4.11 (d, J = 8.80 Hz, 1 H),5.28-5.43 (m, 2 H), 7.65 (d, J = 8.07 Hz, 1 H), 7.78 (d, J = 8.07 Hz, 1H), 8.94 (s, 2 H), 9.78 (s, 1 H), (1 Exchangeable proton not observed).218-I

(R)-3-cyclopropyl-1- (5-((3-(4-methyl-1- oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-2- yl)-1H-pyrazole-4- carbonitrile456.5 S: 1.08, 99.41% R: 1.32, 99.66% XVIII: 19.26, 98.54% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.03-0.88 (m, 2 H), 1.17-1.04 (m, 2 H), 1.87(t, J = 10.3 Hz, 1 H), 2.11-2.02 (m, 1 H), 2.20-2.11 (m, 1 H), 2.24 (s,3 H), 2.77 (t, J = 12.00 Hz, 2 H), 2.94-2.84 (m, 1 H), 3.07-2.96 (m, 1H), 3.74- 3.50 (m, 2 H), 4.07 (d, J = 8.10 Hz, 1 H), 5.48- 5.24 (m, 2H), 7.64 (d, J = 8.10 Hz, 1 H), 7.77 (d, J = 8.10 Hz, 1 H), 8.81 (s, 2H), 9.32 (s, 1 H). (1 Exchangeable proton not observed). 219-I

(R)-3- (difluoromethoxy)-1- (5-((3-(4-methyl-1- oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)pyridin-2-yl)-1H-pyrazole-4- carbonitrile 481.3 S: 1.29, 99.02% R: 1.60, 99.41%XVIII: 7.03, 100% ee ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J = 7.20Hz, 3 H), 2.32 (s, 3 H), 2.93 (dd, J = 12.20, 7.1 Hz, 2 H), 3.03 (br.s., 2 H), 3.42 (br. s., 2 H), 3.78 (br. s., 2 H), 4.73 (br. s., 1 H),5.43 (d, J = 14.20 Hz, 1 H), 7.58 (t, J = 53.50 Hz, 1 H), 7.80-7.67 (m,1 H), 7.90-7.81 (m, 1 H), 8.06 (dd, J = 8.40, 2.10 Hz, 1 H), 8.50 (d, J= 1.70 Hz, 1 H), 9.40 (s, 1 H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ ppm −84.69.220-I

(R)-6-(4-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4-morpholinonicotinonitrile 500.2 S: 0.96, 99.62% R: 1.27, 97.76% XIV:10.79, 99.64% ee ¹H NMR (400 MHz, DMSO-d₆) δ 2.33 (s, 3 H), 2.60 (br.s., 1 H), 3.16 (br. s., 2 H), 3.21 (br. s., 1 H), 3.48-3.34 (m, 2 H),3.60-3.54 (m, 4 H), 3.80-3.74 (m, 4 H), 3.83 (br. s., 2 H), 4.74 (d, J =10.80 Hz, 1 H), 5.52-5.39 (m, 2 H), 7.38 (s, 1 H), 7.75 (d, J = 8.10 Hz,1 H), 7.84 (d, J = 7.80 Hz,1 H), 8.60 (s, 1 H), 7.87 (s, 1 H), 8.63 (s,1 H), (1 Exchangeable proton not observed). 221-I

(R)-3-methyl-1-(5-((3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-2- yl)-1H-pyrazole-4- carbonitrile430.20 G: 11.37, 97.70% F: 10.57, 97.50% XVIII: 18.61, 98.90% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.91 (s, 1 H), 2.15-2.23 (m, 1 H), 2.24 (s, 3H), 2.41 (s, 3 H), 2.72-2.85 (m, 2 H), 2.94 (d, J = 10.52 Hz, 1 H), 3.01(d, J = 9.54 Hz, 1 H), 3.57- 3.71 (m, 2 H), 4.11 (d, J = 9.54 Hz, 1 H),5.29- 5.43 (m, 2 H), 7.66 (d, J = 8.07 Hz, 1 H), 7.78 (d, J = 7.83 Hz, 1H), 8.83 (s, 2 H), 9.34 (s, 1 H). (1 Exchangeable proton not observed).222-I

(R)-4-methyl-5-(4-((6- (4-methyl-1H-1,2,3- triazol-1-yl)pyridin-3-yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 405.00 B: 1.42, 100%A: 1.18, 100% XIV: 7.16, 98.10% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.93(br. s., 1 H), 2.15-2.22 (m, 1 H), 2.24 (s, 3 H) 2.37 (s, 3 H), 2.80 (t,J = 12.47 Hz, 2 H), 2.96 (br. s., 1 H), 3.03 (br. s., 1 H), 3.57-3.71(m, 2H), 4.17 (br. s., 1 H), 5.28-5.43 (m, 2 H), 7.67 (d, J = 7.34 Hz, 1H), 7.78 (d, J = 8.07 Hz, 1 H), 8.01- 8.14 (m, 2 H), 8.49 (s, 1 H), 8.56(s, 1 H). (1 Exchangeable proton not observed). 223-I

(R)-3-methoxy-1-(5- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyridin-2- yl)-1H-pyrazole-4- carbonitrile445.10 B: 1.81, 100% A: 1.48, 100% XIV: 7.96, 98.66% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.85 (t, J = 10.52 Hz, 1 H), 2.09-2.20 (m, 1 H), 2.22 (s,3 H)2.71-2.81 (m, 2H), 2.92 (d, J = 10.03 Hz, 1 H), 2.96-3.03 (m, 1 H),3.51-3.66 (m, 2 H), 4.04 (m, 4 H), 4.08 (d, J = 9.29 Hz, 1 H), 5.36 (d,J = 1.22 Hz, 2 H), 7.65 (d, J = 8.07 Hz, 1 H), 7.73-7.83 (m, 1 H),7.95-8.02 (m, 1 H), 8.39 (d, J = 1.96 Hz, 1 H), 9.21 (s, 1 H). (1Exchangeable proton not observed). 224-I

(R)-4-methyl-5-(4-((2- (4-methyl-1H- imidazol-1- yl)pyrimidin-5-yl)methyl)morpholin- 2-yl)isobenzofuran- 1(3H)-one 406.3 C: 7.89, 98.69%G: 8.99, 98.54% XVIII: 20.31, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.95-2.04 (m, 1 H), 2.17 (s, 3 H), 2.22 (s, 3 H), 2.23-2.36 (m, 1 H),2.70 (d, J = 9.60 Hz, 1 H), 2.90 (d, J = 12.00 Hz, 1 H), 3.57 (s, 2 H),3.65- 3.77 (m, 1 H), 3.97 (d, J = 7.20 Hz, 1 H), 4.82 (d, J = 7.58 Hz, 1H), 5.26-5.45 (m, 2 H), 7.61-7.68 (m, 3 H), 8.47 (dd, J = 8.31, 2.20 Hz,1 H), 8.78 (s, 2 H). 225-I

(R)-1-(5-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyridin-2- yl)-1H-1,2,3-triazole-4-carbonitrile 416.2 B: 1.24, 100% A: 0.99, 100% XIV: 7.96, 97.30% ee ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.95-1.84 (m, 1 H), 2.21-2.14 (m, 1 H),2.24 (s, 3 H), 2.78 (t, J = 9.80 Hz, 2 H), 2.92 (d, J = 9.80 Hz, 1 H),2.99 (s, 1 H), 3.61-3.73 (m, 2 H), 4.10 (d, J = 10.50 Hz, 1 H),5.43-5.29 (m, 2 H), 7.65 (d, J = 7.80 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1H), 8.21-8.08 (m, 2 H), 8.57 (s, 1 H), 9.78 (s, 1 H), (1 Exchangeableproton not observed). 226-I

(R)-3-ethyl-1-(5-((3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyridin-2- yl)-1H-pyrazole-4- carbonitrile443.2 B: 1.67, 100% A: 1.25, 98.15% XIV: 7.78, 99.0% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.30 (t, J = 7.60 Hz, 3 H), 1.85 (t, J = 10.30 Hz, 1 H),2.10-2.20 (m, 1 H), 2.22 (s, 3 H), 2.70-2.85 (m, 4 H), 2.94-2.85 (m, 1H), 3.06-2.95 (m, 1 H), 3.60 (q, J = 13.50 Hz, 2 H), 4.08 (d, J = 10.00Hz, 1 H), 5.24-5.48 (m, 2 H), 7.64 (d, J = 7.80 Hz, 1 H), 7.77 (d, J =8.10 Hz, 1 H), 7.90 (d, J = 8.30 Hz, 1 H), 7.99 (dd, J = 8.40, 2.1 Hz, 1H), 8.41 (d, J = 2.00 Hz, 1 H), 9.27 (s, 1 H), (1 Exchangeable protonnot observed). 227-I

(R)-3-methoxy-1-(5- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-2- yl)-1H-pyrazole-4- carbonitrile446.2 B: 1.17, 95.59% A: 0.97, 94.45% XVIII: 18.87, 97.5% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.87 (t, J = 10.50 Hz, 1 H), 2.11-2.20 (m, 2 H),2.21-2.30 (m, 3 H), 2.77 (t, J = 12.30 Hz, 2 H), 2.84-2.94 (m, 1 H),2.95-3.06 (m, 1 H), 3.53- 3.74 (m, 2 H), 4.03 (s, 3 H), 4.07 (d, J =7.50 Hz, 1 H), 5.27-5.50 (m, 2 H), 7.64 (d, J = 8.00 Hz, 1 H), 7.78 (d,J = 8.00 Hz, 1 H), 8.80 (s, 2 H), 9.30 (s, 1 H). 228-I

(R)-3-ethyl-1-(5-((3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-2- yl)-1H-pyrazole-4- carbonitrile444.3 B: 1.24, 99.34% A: 1.04, 100% XVIII: 18.45, 98.08% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.34 (s, 1 H), 8.83 (s, 2 H), 7.78 (d, J = 8.10 Hz,1 H), 7.65 (d, J = 8.10 Hz, 1 H), 5.47-5.26 (m, 2 H), 4.11 (d, J = 9.30Hz, 1 H), 3.73-3.52 (m, 2 H), 3.06-2.97 (m, 1 H), 2.96-2.87 (m, 1 H),2.85- 2.71 (m, 4 H), 2.24 (s, 3 H), 2.22-2.12 (m, 1 H), 1.90 (t, J =10.30 Hz, 1 H), 1.29 (t, J = 7.60 Hz, 3 H). (1 Exchangeable proton notobserved). 229-I

(R)-3-(difluoromethyl)- 1-(5-((3-(4-methyl-1- oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)pyrimidin-2-yl)-1H-pyrazole-4- carbonitrile 466.3 B: 1.25, 95.14% A: 1.02, 96.07%XIV: 10.12, 98.00% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.90 (t, J = 9.80Hz, 1 H), 2.09-2.22 (m, 1 H), 2.24 (s, 3 H), 2.79 (t, J = 11.00 Hz, 2H), 2.92 (d, J = 9.80 Hz, 1 H), 2.96-3.05 (m, 1 H), 3.59-3.76 (m, 2 H),4.09 (d, J = 8.80 Hz, 1 H), 5.21-5.48 (m, 2 H), 7.23-7.49 (t, J = 52.80Hz, 1 H), 7.65 (d, J = 7.80 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1H), 8.90(s, 2 H), 9.62 (s, 1 H), (1 Exchangeable proton not observed). ¹⁹F NMR(400 MHz, DMSO-d₆) δ ppm −114.59. 230-I

(R)-4-methyl-2-(4-((3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)pyrimidine-5- carbonitrile430.2 B: 1.05, 98.55% A: 0.76, 97.72% XVIII: 18.27, 99.00% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.91 (s, 1 H), 2.27 (s, 4 H), 2.70 (s, 3 H),2.86 (br. s., 2 H), 2.99 (s, 1 H), 3.08 (br. s., 1 H), 3.56 (br. s., 2H), 4.23 (br. s., 1 H), 5.22-5.50 (m, 2 H), 7.68 (d, J = 8.30 Hz, 1 H),7.76 (d, J = 8.30 Hz,1 H), 7.89 (s, 1 H), 8.59 (s, 1 H), ( 9.20 (s, 1H), (1 Exchangeable proton not observed). 231-I

(R)-2-(4-((3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-5-(pyrrolidin-1-yl)isonicotinonitrile 484.3 B: 1.45, 99.72% A: 1.09, 100% XVIII: 15.10,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.97-2.01 (m, 4 H), 2.34 (s, 4H), 3.05 (d, J = 10.30 Hz, 2 H), 3.17 (s, 2 H), 3.40 (br. s., 1 H), 3.67(br. s., 5 H), 4.72 (br. s., 1 H), 5.45 (d, J = 12.70 Hz, 2 H), 7.03 (s,1 H), 7.69-7.76 (m, 1 H), 7.79 (s, 1 H), 7.85 (d, J = 7.80 Hz, 1 H),8.41 (s, 1 H), 8.53 (s, 1 H), 8.88 (s, 1 H), 9.33 (s, 1 H). 232-I

4-methyl-6-(4-((3-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)-4-oxopiperidin-1- yl)methyl)-1H-pyrazol- 1-yl)nicotinonitrile442.2 R: 1.34, 62.00% S: 1.86, 100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.15(s, 3 H), 2.35 (d, J = 14.43 Hz, 1 H), 2.58 (s, 3 H), 2.62-2.71 (m, 2H), 2.73-2.89 (m, 1 H), 3.20 (br. s., 2 H), 3.75 (s, 2 H), 4.27 (dd, J =11.37, 5.50 Hz, 1 H), 5.30-5.44 (m, 2 H), 7.42 (d, J = 8.07 Hz, 1 H),7.62 (d, J = 7.58 Hz, 1 H), 7.93 (s, 1 H), 7.99 (s, 1 H), 8.62 (s, 1 H),8.84 (s, 1 H). 233-I

(R)-6-(3- (difluoromethyl)-4-((3- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4-methylnicotinonitrile 479.1 R: 1.59, 99.30% S: 1.94, 98.00% XVIII:10.70, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.89 (br. s., 1 H), 2.19(br. s., 1 H), 2.24 (s, 3 H), 2.60 (s, 3 H), 2.76-2.89 (m, 2 H), 2.94(br. s., 1 H), 3.03 (br. s., 1 H), 3.51-3.67 (m, 2 H), 4.12 (br. s., 1H), 5.36 (d, J = 3.18 Hz, 2 H), 7.08-7.39 (m, 1 H), 7.66 (d, J = 7.58Hz, 1 H), 7.77 (d, J = 7.83 Hz, 1 H), 8.02 (s, 1 H), 8.66 (s, 1 H), 8.89(s, 1 H). (1 Exchangeable proton not observed). ¹⁹F NMR (400 MHz,DMSO-d₆) δ ppm −114.2. 234-I

(R)-5-(4-((2-(1H-1,2,4- triazol-1-yl)pyrimidin- 5-yl)methyl)piperazin-2-yl)-4- methylisobenzofuran- 1(3H)-one 392.1 R: 0.93, 97.00% S: 1.06,93.50% XIV: 7.53, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.86-1.95 (m,1 H), 2.13-2.22 (m, 1 H), 2.25 (s, 3 H), 2.64-2.84 (m, 2 H), 2.86-3.05(m, 2 H), 3.65 (d, J = 8.07 Hz, 2 H), 4.09 (d, J = 8.31 Hz, 1 H), 5.36(d, J = 4.40 Hz, 2 H), 7.65 (d, J = 7.83 Hz, 1 H), 7.78 (d, J = 7.58 Hz,1 H), 8.32 (s, 1 H), 8.87 (s, 2 H), 9.43 (s, 1 H). (1 Exchangeableproton not observed). 235-I

(R)-5-(4-((6-(4 (difluoromethyl)-1H- imidazol-1-yl)pyridin-3-yl)methyl)piperazin- 2-yl)-4- methylisobenzofuran- 1(3H)-one 440.1 R:1.19, 95.40% S: 1.45, 98.40% XIV: 6.79, 88.00% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.79-1.90 (m, 1 H), 2.09-2.19 (m, 1 H), 2.23 (s, 3 H),2.72-2.80 (m, 2 H), 2.86-2.93 (m, 1 H), 2.94-3.03 (m, 1 H), 3.49-3.53(m, 2 H), 4.07 (d, J = 7.58 Hz, 1 H), 5.36 (s, 2 H), 6.82-7.14 (m, 1 H),7.64 (d, J = 7.83 Hz, 1 H), 7.78 (d, J = 8.07 Hz, 1 H), 7.86 (d, J =8.07 Hz, 1 H), 7.97 (dd, J = 8.31, 2.20 Hz, 1 H), 8.29 (s, 1 H), 8.44(d, J = 1.71 Hz, 1 H), 8.62 (s, 1 H). (1 Exchangeable proton notobserved). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −112.0. 236-I

(R)-4-methyl-5-(4-((2- (4-(trifluoromethyl)- 1H-imidazol-1-yl)pyrimidin-5- yl)methyl)piperazin-2- yl)isobenzofuran- 1(3H)-one 459.1A: 1.34, 96.60% B: 1.65, 97.40% XIV: 6.82, 97.00% ee ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.94 (br. s., 1 H), 2.21 (br. s., 1 H), 2.25 (s, 3 H), ,2.82 (br. s., 2 H), 2.91-3.08 (m, 2 H), 3.66 (d, J = 1 5.87 Hz, 2 H),4.13 (br. s., 1 H), 5.37 (d, J = 6.36 Hz, 2 H), 7.67 (d, J, = 8.31 Hz, 1H), 7.78 (d, J = 8.07 Hz, 1 H), 8.52 (s, 1 H), 8.76 (s, 1 H), 8.86 (s, 2H). (1 Exchangeable proton not observed). ¹⁹F NMR (400 MHz, DMSO-d₆) δppm −61.7. 237-I

(R)-6-(3-cyclopropyl- 4-((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methylnicotinonitrile469.1 R: 1.57, 97.90% S: 2.03, 98.00% XVII: 8.49, 100% ee ¹H NMR (400MHz, DMSO-d6) δ ppm 0.89-0.99 (m, 4 H), 1.84 (t, J = 10.03 Hz, 1 H),2.05-2.19 (m, 2 H), 2.25 (s, 3 H), 2.54 (s, 3 H), 2.76-2.95 (m, 3 H),3.01 (d, J = 12.23 Hz, 1 H), 3.54 (d, J = 9.78 Hz, 2 H), 4.08 (d, J =8.07 Hz, 1 H), 5.36 (s, 2 H), 7.64 (d, J = 8.07 Hz, 1 H), 7.74- 7.83 (m,2 H), 8.39 (s, 1 H), 8.76 (s, 1 H). (1 Exchangeable proton notobserved). 238-I

1′-methyl-5-(((3S,5R)- 3-methyl-5-(4-methyl- 1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-[2,3′-bipyridin]-6′(1′H)-one 445.2 R: 0.46, 100% S: 1.02, 96.10% ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.15-1.24 (m, 3 H), 2.20-2.24 (m, 4 H), 2.52- 2.55(m, 2 H), 2.96 (br. s., 3 H), 3.54 (s, 3 H), 3.68 (br. s., 2 H),5.54-5.31 (m, 2 H), 6.50 (d, J = 9.30 Hz, 1 H), 7.79 (s, 4 H), 8.16 (dd,J = 9.40, 2.60 Hz, 1 H), (8.53 (d, J = 2.70 Hz, 2 H). (1 Exchangeableproton not observed). 239-I

(R)-4-methyl-6-(4-((3- (1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)nicotinonitrile 415.2 R:0.93, 95.50% S: 1.23, 95.40% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.83-1.97(m, 1 H), 2.06-2.18 (m, 1 H), 2.58 (s, 3 H), 2.75-2.92 (m, 3 H), 3.00(d, J = 10.5 Hz, 1 H), 3.53 (s, 2H), 3.96 (d, J = 8.6 Hz, 1 H), 5.37 (s,2 H), 7.61 (d, J = 8.10 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J = 7.80 Hz, 1H), 7.84 (s, 1 H), 7.98 (s, 1 H), 8.53 (s, 1 H), 8.83 (s, 1 H). (1Exchangeable proton not observed). 240-I

4-methyl-6-(4-(((6R)- 2-methyl-6-(4-methyl- 1-oxo-1,3-dihydroisobenzofuran- 5- yl)morpholino)methyl)- 1H-pyrazol-1-yl)nicotinonitrile (Diastereomer-I) 444.2 R: 1.16, 100% S: 1.78, 94.30%XVIII: 14.40, 98.00% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (d, J =6.10 Hz, 3 H), 1.86 (br. s., 2 H), 2.24 (s, 3 H), 2.58 (s, 3 H), 2.88(d, J = 11.50 Hz, 2H), 3.56 (br. s., 2 H), 3.84 (br. s., 1 H), 4.87 (d,J = 10.00 Hz, 1 H), 5.49-5.26 (m, 2 H), 7.61 (d, J = 8.10 Hz, 1 H), 7.68(d, J = 7.80 Hz, 1 H), 7.87 (s, 1 H), 7.99 (s, 1 H), 8.55 (br. s., 1 H),8.83 (s, 1 H). 241-I

(R)-3-methyl-1-(6-((3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyridin-3- yl)-1H-pyrazole-4- carbonitrile429.1 R: 0.94, 98.10% S: 1.18, 94.30% ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.34 (s, 3 H), 2.41 (s, 3 H), 2.60 (d, J = 13.00 Hz, 2 H), 3.09 (d, J =12.50 Hz, 2 H), 3.42 (br. s., 2 H), 3.89 (br. s., 2H), 4.78 (br. s., 1H), 5.54-5.34 (m, 2 H), 7.67 (d, J = 8.30 Hz, 1 H), 7.76 (d, J = 8.10Hz, 1 H), 7.85 (d, J = 8.10 Hz, 1 H), 8.24 (dd, J = 8.60, 2.4 Hz, 1 H),9.01 (d, J = 2.20 Hz, 2 H), 9.29 (s, 1 H). 242-I

(R)-4-methyl-1-(5-((3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyridin-2- yl)-1H-pyrazole-3- carbonitrile429.1 R: 1.54, 97.80% S: 1.89, 95.10% XVIII: 14.07, 100% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.85 (t, J = 9.66 Hz, 1 H), 2.11-2.19 (m, 1 H), 2.23(d, J = 4.16 Hz, 6 H), 2.71-2.82 (m, 2 H), 2.90 (t, J = 11.37 Hz, 1 H),2.99 (d, J = 11.00 Hz, 1 H), 3.54-3.68 (m, 2 H), 4.08 (d, J = 7.34 Hz, 1H), 5.36 (s, 2 H), 7.64 (d, J = 8.07 Hz, 1 H), 7.78 (d, J = 8.07 Hz, 1H), 7.91-7.96 (m, 1 H), 7.98- 8.03 (m, 1 H), 8.43 (s, 1 H), 8.69 (s, 1H). (1 Exchangeable proton not observed). 243-I

(R)-4-methyl-1-(5-((3- (4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)pyrimidin-2- yl)-1H-pyrazole-3- carbonitrile431.0 R: 1.00, 98.90% S: 1.24, 99.30% XVIII: 9.09, 100% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.97-1.82 (m, 1 H), 2.13-2.21 (m, 1 H), 2.22- 2.29(m, 6 H), 2.80 (t, J = 11.60 Hz, 2 H), 2.88- 2.96 (m, 1 H), 2.97-3.05(m, 1 H), 3.55-3.74 (m, 2 H), 4.10 (d, J = 8.60 Hz, 1 H), 5.26-5.48 (m,2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1 H), 8.72 (d, J= 0.70 Hz, 1 H), 8.86 (s, 2 H), (1 Exchangeable proton not observed).244-II

4-methyl-6-(4-((2- methyl-5-(4-methyl-1- oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-pyrazol- 1-yl)nicotinonitrile(Enantiomer-II) 443.2 R: 1.35, 100% S: 1.73, 100% XVIII: 9.09, 100% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (d, J = 6.10 Hz, 3 H), 2.30-2.33(m, 3 H), 2.58 (s, 3 H), 2.79 (br. s., 1 H), 3.06-3.15 (m, 3 H), 3.89(d, J = 14.40 Hz, 2 H), 3.99 (d, J = 14.90 Hz, 1 H), 4.70 (d, J = 8.80Hz, 1 H), 5.50-5.39 (m, 2 H), 7.66 (d, J = 8.10 Hz, 1 H), 7.83 (d, J =8.10 Hz, 1 H), 7.91 (s, 1 H), 8.00 (s, 1 H), 8.65 (s, 1 H), 8.84 (s, 1H), (1 Exchangeable proton not observed). 245-I

6-(3-(difluoromethyl)- 4-(((3R,4R)-4-hydroxy- 3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperidin-1- yl)methyl)-1H-pyrazol- 1-yl)-4-methylnicotinonitrile 494.2 R: 1.18, 100% S: 1.71, 98.90% XXVI: 4.36,100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64 (d, J = 9.30 Hz, 1 H), 1.92(br. s., 1 H), 2.00- 2.12 (m, 1 H), 2.23 (s, 4 H), 2.55 (s, 3 H), 2.58-2.66 (m, 1 H), 2.72 (d, J = 11.70 Hz, 1 H), 2.95 (d, J = 10.30 Hz, 1 H),3.01-3.14 (m, 1 H), 3.46- 3.67 (m, 2 H), 3.75 (br. s., 1 H), 4.60 (d, J= 5.40 Hz, 1 H), 5.48-5.24 (m, 2H), 7.54 (d, J = 7.60 Hz, 1 H), 7.63 (d,J = 8.30 Hz, 1 H), 8.02 (s, 1 H), 8.65 (s, 1 H), 8.90 (s, 1 H). ¹⁹F NMR(400 MHz, DMSO-d₆) δ ppm −114.00 246-I

6-(4-(((3S,5R)-4- hydroxy-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2H-1,2,3-triazol-2-yl)-4- methylnicotinonitrile 460.3 R: 0.76, 97.20% S: 1.30,93.30% XXV: 15.22, 98.00% ee. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.11(m, 3 H), 2.26 (s, 3 H), 2.30-2.33 (m, 1 H) 2.55-2.66 (m, 4 H), 2.74 (s,1 H), 2.80 (br. s., 1 H), 4.25 (br. s., 3 H), 5.31-5.49 (m, 2 H), 7.72(d, J = 8.10 Hz, 1 H), 7.80 (d, J = 7.80 Hz, 1 H), 7.96-8.22 (m, 2 H),8.33 (s, 1 H), 8.92-9.05 (m, 1 H), (1 Exchangeable proton not observed).247-I

4′-methyl-4-(((3S,5R)- 3-methyl-5-(4-methyl- 1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2-oxo-2H-[1,2′-bipyridine]-5′- carbonitrile 470.2 R: 1.18, 96.30% S: 1.52, 100%XIV: 3.45, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (d, J = 6.10 Hz,3 H), 2.32-2.25 (m, 3 H), 2.58 (s, 3 H), 2.75-2.72 (m, 1 H), 2.79 (d, J= 11.50 Hz, 2 H), 2.90 (s, 1 H), 3.01 (br. s., 1 H), 3.42 (s, 2 H), 4.20(d, J = 10.30 Hz, 1 H), 5.39 (s, 2 H), 6.51-6.39 (m, 2 H), 7.67 (d, J =7.80 Hz, 1 H), 7.82 (d, J = 8.10 Hz, 1 H), 7.91 (d, J = 7.30 Hz, 1 H),8.01 (s, 1 H), 8.99 (s, 1 H), (1 Exchangeable proton not observed).248-I

N-(1-((1-(5-cyano-4- methylpyridin-2-yl)- 1H-pyrazol-4- yl)methyl)-3-(4-methyl-1-oxo-1,3- dihydroisobenzofuran- 5-yl)piperidin-4- yl)acetamide(Diastereomer-II Enantiomer-I) 485.3 S: 1.28, 100% R: 0.94, 100% XXV:4.99, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (s, 3 H), 1.65-1.57(m, 1 H), 1.98-1.79 (m, 2 H), 2.18 (t, J = 11.70 Hz, 1 H), 2.24 (s, 3H), 2.56 (s, 3 H), 2.98-2.85 (m, 2 H), 3.22-3.13 (m, 2 H), 4.13-4.04 (m,1 H), 4.17 (d, J = 4.60 Hz, 1 H), 5.42-5.23 (m, 2 H), 7.39 (d, J = 7.80Hz, 1 H), 7.57 (d, J = 7.80 Hz, 1 H), 7.69 (d, J = 8.80 Hz, 1 H), 7.83(s, 1 H), 7.95 (s, 1 H), 8.50 (s, 1 H), 8.80 (s, 1 H). 249-I

3-(6-(4-(((3S,5R)-3- methyl-5-(4-methyl-1- oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol-1-yl)pyridin-2- yl)oxazolidin-2-one 489.3 S: 1.41, 93.18% R: 1.01,94.16% VIII: 5.38, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J =6.10 Hz, 3 H), 1.72-1.75 (m, 2 H), 2.31 (s, 3 H), 2.80 (br. s., 2 H),2.98 (br. s., 1 H), 3.50- 3.48 (m., 2 H), 4.17 (d, J = 9.80 Hz, 1 H),4.39- 4.23 (m, 2 H), 4.61-4.39 (m, 2 H), 5.38 (s, 2 H), 7.59 (dd, J =7.10, 1.70 Hz, 1 H), 7.66 (d, J = 8.10 Hz, 1 H), 7.74 (s, 1 H), 7.81 (d,J = 8.10 Hz, 1 H), 8.09-7.91 (m, 2 H), 8.47 (s, 1 H), (1 Exchangeableproton not observed). 250-I

6-(4-(((3R,4R)-4- hydroxy-3-(4-methyl- 1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-3-methyl-2- oxo-2,3-dihydro-1H-imidazol-1-yl)-4- methylnicotinonitrile 474.4 S: 1.44, 100% R: 0.95,100% VIII: 5.92, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (s, 2 H),1.69-1.54 (m, 1 H), 2.03-1.87 (m, 1 H), 2.11 (t, J = 11.40 Hz, 1 H),2.31-2.16 (m, 4 H), 2.78 (d, J = 11.00 Hz, 1 H), 2.97 (d, J = 12.50 Hz,1 H), 3.05 (td, J = 10.40, 3.40 Hz, 1 H), 3.29 (s, 3 H), 3.50-3.36 (m, 2H), 3.81-3.70 (m, 1 H), 4.60 (d, J = 5.40 Hz, 1 H), 5.45-5.24 (m, 2 H),7.26 (s, 1 H), 7.55 (d, J = 7.80 Hz, 1 H), 7.64 (d, J = 7.80 Hz, 1 H),8.44 (s, 1 H), 8.76 (s, 1 H), (1 Exchangeable proton not observed).251-I

3-(2-methyl-6-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol-1-yl)pyridin-4- yl)oxazolidin-2-one 503.2 S: 1.39, 100% R: 0.95, 100%XV: 4.95, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (d, J = 4.40 Hz,3 H), 1.73 (br. s., 2 H), 2.27 (s, 3 H), 2.48 (s, 4 H), 2.81 (d, J =9.00 Hz, 2 H), 2.98 (br. s., 1 H), 3.52 (br. s., 2 H), 4.26-4.03 (m, 3H), 4.57-4.44 (m, 2 H), 5.38 (s, 2 H), 7.27 (d, J = 1.70 Hz, 1 H), 7.66(d, J = 8.10 Hz, 1 H), 7.72 (s, 1 H), 7.80 (d, J = 8.10 Hz, 1 H), 8.06(s, 1 H), 8.45 (s, 1 H). 252-I

N-methyl-N-(6-(4- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazol-1-yl)pyridin-2- yl)methanesulfonamide 511.3 S: 1.42, 97.31% R: 1.00,97.44% XV: 3.94, 98.52% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J =6.10 Hz, 3 H), 1.73 (br. s., 2 H), 2.26 (s, 3 H), 2.74 (s, 1 H), 2.82(d, J = 9.80 Hz, 2 H), 2.97 (br. s., 1 H), 3.26-3.22 (m, 3 H), 3.38 (s,3 H), 3.55-3.46 (m, 2 H), 4.17 (d, J = 8.60 Hz, 1 H), 5.44-5.29 (m, 2H), 7.33 (d, J = 7.80 Hz, 1 H), 7.70-7.60 (m, 2 H), 7.76 (s, 1 H), 7.81(d, J = 8.10 Hz, 1 H), 8.04-7.95 (m, 1 H), 8.44 (s, 1 H). 253-I

5-((2R,6S)-4-((1-(4- (1,1- dioxidoisothiazolidin- 2-yl)-6-methylpyridin-2-yl)-1H-pyrazol-4- yl)methyl)-6- methylpiperazin-2-yl)- 4-methylisobenzofuran- 1(3H)-one 537.3 S: 1.41, 96.07% R: 0.99, 97.18%XVII: 8.82, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J = 6.40Hz, 3 H), 1.24-1.20 (s, 2 H), 1.71 (t, J = 10.10 Hz, 2 H), 2.48-2.40 (m,6 H), 2.80 (d, J = 10.80 Hz, 2 H), 2.97 (br. s., 1 H), 3.56- 3.44 (m, 2H), 3.64 (t, J = 7.20 Hz, 2 H), 3.86 (t, J = 6.60 Hz, 2 H), 4.16 (d, J =8.80 Hz, 1 H), 5.38 (s, 2 H), 6.87 (d, J = 1.70 Hz, 1 H), 7.52 (d, J =1.70 Hz, 1 H), 7.64 (d, J = 8.10 Hz, 1 H), 7.70 (s, 1 H), 7.80 (d, J =8.10 Hz, 1 H), 8.42 (s, 1 H), (1 Exchangeable proton not observed).254-I

1-(2-methoxypyridin- 4-yl)-4-(((3S,5R)-3- methyl-5-(4-methyl-1- oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)pyrrolidin-2- one(Diastereomer-I) 451.3 S: 1.23, 100% R: 0.47, 100% XXV: 7.16, 97.00% ee¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 (d, J = 4.40 Hz, 3 H), 1.73 (q, J =10.60 Hz, 2 H), 2.31 (s, 3 H), 2.43-2.32 (m, 3 H), 2.75-2.59 (m, 2 H),2.81 (t, J = 11.50 Hz, 2 H), 2.96 (br. s., 1 H), 3.55 (dd, J = 9.80,5.60 Hz, 1 H), 3.87-3.77 (m, 3 H), 3.92 (dd, J = 9.70, 7.70 Hz, 1 H),4.15 (d, J = 8.60 Hz, 1 H), 5.48-5.30 (m, 2 H), 7.05 (d, J = 1.50 Hz, 1H), 7.36 (dd, J = 6.00, 1.80 Hz, 1 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.82(d, J = 7.80 Hz, 1 H), 8.08 (d, J = 5.90 Hz, 1 H), (1 Exchangeableproton not observed). 255-I

(R)-4-methoxy-6-(4- ((3-(4-methyl-1-oxo- 1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-1,2,3- triazol-1- yl)nicotinonitrile446.2 G: 12.33, 99.40% E: 10.51, 98.80% XVIII: 20.06, 100% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.84-1.94 (m, 1 H), 2.13-2.22 (m, 1 H), 2.26(s, 3 H), 2.78-2.92 (m, 3 H), 2.93-3.01 (m, 1 H), 3.74 (s, 2 H),4.03-4.09 (m, 1 H), 4.16 (s, 3 H), 5.37 (s, 2 H), 7.64 (d, J = 8.03 Hz,1 H), 7.76 (d, J = 8.03 Hz, 1 H), 7.88 (s, 1 H), 8.77 (s, 1 H), 8.88 (s,1 H), (1 Exchangeable proton not observed). 256-II

6-(4-((2,2-dimethyl-6- (4-methyl-1-oxo-1,3- dihydroisobenzofuran- 5-yl)morpholino)methyl)- 1H-pyrazol-1-yl)-4- methylnicotinonitrile(Enantiomer-II) 458.0 G: 14.03, 95.39% C: 12.55, 95.71% XIII: 3.82,95.27% ee ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.20 (s, 3 H), 1.41 (s, 3 H),1.67-1.77 (m, 1 H), 1.87-1.93 (m, 1 H), 2.26 (s, 3 H), 2.60 (s, 3 H),2.69-2.72 (m, 1 H), 2.93-2.96 (m, 1 H), 3.42-3.67 (m, 2 H), 5.08 (d, J =8.69 Hz, 1 H), 5.38 (s, 2 H), 7.64 (q, J = 7.93 Hz, 2 H), 7.87 (d, J =2.40 Hz 1 H), 7.99 (s, 1 H), 8.55 (d, J = 2.40 Hz 1 H), 8.84 (s, 1 H).257-I

N-(1-((1-(5-cyano-4- methylpyridin-2-yl)- 1H-pyrazol-4- yl)methyl)-5-(4-methyl-1-oxo-1,3- dihydroisobenzofuran- 5-yl)piperidin-3- yl)acetamide(Enantiomer-I) 485.1 R: 1.08, 100% S: 1.43, 100% XXI: 2.38, 100% ee. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.37 (m, 1 H), 1.79 (s, 3 H), 1.88 (d,J = 12.00 Hz, 1 H), 1.98 (t, J = 10.90 Hz, 1 H), 2.26 (s, 3 H), 2.59 (s,3 H), 2.86 (d, J = 11.00 Hz, 1 H), 3.02 (br. s., 1 H), 3.21 (s, 1 H),3.61 (s, 2 H), 3.93 (s, 1 H), 5.38 (s, 2 H), 7.42 (d, J = 8.10 Hz, 1 H),7.66 (d, J = 8.30 Hz, 1 H), 7.81 (d, J = 7.60 Hz, 1 H), 7.87 (s, 1 H),8.00 (s, 1 H), 8.55 (s, 1 H), 8.84 (s, 1 H), (1 Exchangeable proton notobserved). 258-I

1-((1-(5-cyano-4- methylpyridin-2-yl)- 1H-pyrazol-4- yl)methyl)-3-(4-methyl-1-oxo-1,3- dihydroisobenzofuran- 5-yl)piperidin-4-ylmethylcarbamate (Enantiomer-I) 501.5 R: 1.10, 95.00% S: 1.55, 96.00%XXII: 6.23, 94.05% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66 (d, J = 11.70Hz, 1 H), 2.20-1.99 (m, 2 H), 2.33-2.23 (m, 4 H), 2.42 (d, J = 4.60 Hz,3 H), 2.58 (s, 3 H), 2.84 (d, J = 9.50 Hz, 1 H), 2.97 (d, J = 11.00 Hz,1 H), 3.50-3.68 (m, 2 H), 5.00-4.75 (m, 1 H), 5.36 (s, 2 H), 6.73 (d, J= 4.40 Hz, 1 H), 7.52 (d, J = 7.80 Hz, 1 H), 7.64 (d, J = 8.10 Hz, 1 H),7.87 (s, 1 H), 7.99 (s, 1 H), 8.54 (s, 1 H), 8.83 (s, 1 H), (1Exchangeable proton not observed). 259-I

4-methyl-6-(3- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1,2,4- oxadiazol-5-yl)nicotinonitrile 445.2 R: 1.05, 100% S: 1.35, 99.10% ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.12-0.93 (m, 3 H), 1.94 (dt, J = 17.20, 10.40 Hz, 2 H),2.23-2.34 (m, 3 H), 2.68-2.60 (m, 3 H), 2.88 (t, J = 12.00 Hz, 2 H),3.05-2.93 (m, 1 H), 3.84 (s, 2 H), 4.17 (d, J = 8.10 Hz, 1 H), 5.47-5.32(m, 2 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.80 (d, J = 8.10 Hz, 1 H), 8.40(s, 1 H), 8.74 (br. s., 1 H), 9.15 (s, 1 H). 260-I

(R)-1-(5-cyano-4- methoxypyridin-2-yl)- N-methyl-4-((3-(4-methyl-1-oxo-1,3- dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H-pyrazole-3- carboxamide 502.2 R: 0.94, 100% S: 1.22, 98.74% XIV: 9.16,98.74% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.95 (br. s., 1 H), 2.21 (br.s., 1 H), 2.27 (s, 4 H), 2.96-2.77 (m 6 H) 3.04 (br. s., 1 H) 3.76 (br.s 2 H), 4.14 (s, 3 H), 5.42-5.33 (m, 2 H), 7.67 (d, J = 7.30 Hz, 1 H),7.73 (s, 1 H), 7.77 (d, J = 8.30 Hz, 1 H), 8.60 (s, 1 H), 8.78 (s, 1 H),9.17 (br. s., 1 H), (1 Exchangeable proton not observed). 261-II

6-(4-((3- (hydroxymethyl)-5-(4- methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-1- yl)methyl)-1H-pyrazol- 1-yl)-4- methylnicotinonitrile(Diastereomer-II: Enantiomer-II) 458.2 R: 1.08, 100% S: 1.44, 100%XXVII: 4.90, 100% ee. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.45 (m, 1H), 1.78 (d, J = 12.20 Hz, 1 H), 2.14 (br. s., 1 H), 2.28 (s, 3 H),2.59-2.54 (m, 1 H), 2.61 (s, 3 H), 3.11 (d, J = 7.60 Hz, 1 H), 3.37-3.28 (m, 2 H), 3.56-3.46 (m, 1 H), 3.37-3.43 (m, 2 H), 4.39 (br. s., 2H), 4.88 (br. s., 1 H), 5.41 (s, 2 H), 7.53 (d, J = 8.10 Hz, 1 H), 7.73(d, J = 8.10 Hz, 1 H), 8.06 (s, 2 H), 9.01-8.86 (m, 2 H). 262-I

(R)-1-(5-cyano-4- methoxypyridin-2-yl)- 4-((3-(4-methyl-1-oxo- 1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-1H- pyrazole-3-carboxamide 488.2 R: 0.86, 100% S: 1.13, 100% XIV: 9.31, 100% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.34 (s, 4 H), 2.93 (dd, J = 12.20, 6.40 Hz, 1H), 3.11 (d, J = 11.70 Hz, 2 H), 3.97 (br. s., 2 H), 4.13 (s, 3 H), 4.74(br. s., 1 H), 5.57-5.28 (m, 2 H), 7.56 (br. s., 1 H), 7.72 (d, J = 8.10Hz, 1 H), 7.83 (d, J = 7.80 Hz, 1 H), 7.89 (s, 1 H), 8.11 (br. s., 1 H),8.65 (br. s., 1 H), 8.79 (s, 1 H), 8.87 (br. s., 1 H), 9.37 (br. s., 1H), (1 Exchangeable proton not observed). 263-I

(R)-4-(methoxy-d3)-6- (4-((3-(4-methyl-1- oxo-1,3- dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-1H-1,2,3- triazol-1- yl)nicotinonitrile449.2 R: 0.95, 100%, S: 1.3, 98.70% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91(s, 1 H), 2.27 (s, 3 H), 2.45 (br. s., 1 H), 2.86 (br. s., 3 H), 3.00(br. s., 1 H), 3.76 (s, 2 H), 4.12 (br. s., 1 H), 5.44-5.31 (m, 2H),7.66 (d, J = 8.10 Hz, 1 H), 7.76 (d, J = 8.30 Hz, 1 H), 7.88 (s, 1 H),8.78 (s, 1 H), 8.88 (s, 1 H), (1 Exchangeable proton not observed).264-I

(R)-4-methyl-5-(4-((6- (3-methyl-1,2,4- oxadiazol-5-yl)pyridin-3-yl)methyl)piperazin- 2-yl)isobenzofuran- 1(3H)-one 406.2 R: 0.85,98.08% S: 1.07, 100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.99 (br. S., 1 H),2.25 (s, 4 H), 2.45 (s, 3 H), 2.81 (t, J = 12.80 Hz, 2 H), 3.11-2.95 (m,2 H), 3.63-3.78-(m, 2 H), 4.20 (br. s., 1 H), 5.44- 5.30 (m, 2 H), 7.68(d, J = 7.60 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1 H), 8.03 (dd, J = 8.10,2.00 Hz, 1 H), 8.20 (d, J = 8.10 Hz, 1 H), 8.75 (d, J = 1.50 Hz, 1 H),(1 Exchangeable proton not observed). 265-I

2-methyl-4-(5- (((3S,5R)-3-methyl-5- (4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1- yl)methyl)-2H-tetrazol-2-yl)benzonitrile 444.2 R: 1.23, 97.88% S: 1.63, 100% VIII: 4.75, 98.84%ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J = 5.90 Hz, 3 H), 2.00-1.78(m, 2 H), 2.32-2.21 (m, 3 H), 2.66-2.56 (m, 3 H), 3.05- 2.79 (m, 3 H),4.04-3.86 (m, 2 H), 4.17 (d, J = 2.7 Hz, 1 H), 5.39 (s, 2 H), 7.66 (d, J= 7.80 Hz, 1 H), 7.79 (d, J = 8.10 Hz, 1 H), 8.15-7.99 (m, 2 H), 8.23(s, 1 H), (1 Exchangeable proton not observed).

Intermediate 193: 6-(5-formylisoxazol-3-yl)-4-methoxynicotinonitrile

Intermediate 193A: methyl 5-cyano-4-methoxypicolinate

Intermediate 193A was prepared (6.00 g, 52.60%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 16A andstarting from 6-chloro-4-methoxynicotinonitrile (10.00 g, 59.30 mmol).¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.93 (s, 3H), 4.11 (s, 3H), 7.82 (s,1H), 8.94 (s, 1H). LCMS (Method-1): retention time 0.79 min, [M+H]192.9.

Intermediate 193B: 6-(hydroxymethyl)-4-methoxynicotinonitrile

To a stirred solution of methyl 5-cyano-4-methoxypicolinate (3.00 g,15.61 mmol) in a mixture of THF (50 mL) and EtOH (50 mL) was addedcalcium chloride (4.33 g, 39.00 mmol) followed by NaBH₄ (2.36 g, 62.40mmol) and the resulting reaction mixture was stirred at ambienttemperature for 16 h. The reaction mixture was concentrated to drynessunder reduced pressure, diluted with saturated solution of NaHCO₃ (100mL) and extracted with ethyl acetate (3×100 mL). The combined organiclayer was washed with brine (50 mL), dried over anhydrous sodium sulfateand evaporated under reduced pressure to obtain Intermediate 193B (1.80g, 70.20%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.02(s, 3H), 4.60 (d, J=3.00 Hz, 2H), 5.72 (t, J=3.50 Hz, 1H), 7.30 (s, 1H),8.71 (s, 1H). LCMS (Method-1): retention time 0.56 min, [M+H] 164.9.

Intermediate 193C: 6-formyl-4-methoxynicotinonitrile

Intermediate 193C was prepared (1.70 g, 96.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 193B (1.80 g, 10.96 mmol) and Dess-Martinperiodinane (6.98 g, 16.45 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.12(s, 3H), 7.70 (s, 1H), 9.06 (s, 1H), 9.99 (s, 1H). LCMS: The compounddid not ionize well.

Intermediate 193D: (E)-6-((hydroxyimino)methyl)-4-methoxynicotinonitrile

Intermediate 193D was prepared (0.90 g, 78.00%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 110B andstarting from Intermediate 193C (1.05 g, 6.48 mmol) and hydroxylaminehydrochloride (0.54 g, 7.77 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.04(s, 3H), 7.50 (s, 1H), 8.11 (s, 1H), 8.81 (s, 1H), 12.14 (s, 1H). LCMS(Method-I): retention time 0.73 min, [M+H] 177.9.

Intermediate 193E:6-(5-(hydroxymethyl)isoxazol-3-yl)-4-methoxynicotinonitrile

Intermediate 193E was prepared (0.15 g, 25.50%) as an off-white solid,by using a similar synthetic protocol as that of Intermediate 110C andstarting from Intermediate 193D (0.77 g, 3.75 mmol) and prop-2-yn-1-ol(0.14 g, 2.54 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.12 (s, 3H), 4.66(d, J=5.00 Hz, 2H), 5.77 (t, J=5.00 Hz, 1H), 6.97 (s, 1H), 7.79 (s, 1H),8.95 (s, 1H). LCMS (Method-I): retention time 0.84 min, [M+H]232.0.

Intermediate 193

Intermediate 193 was prepared (0.17 g, 90.00%) as an off-white solid, byusing a similar synthetic protocol as that of Intermediate 9 andstarting from Intermediate 193E (0.19 g, 0.82 mmol) and Dess-Martinperiodinane (0.52 g, 1.23 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.12(s, 3H), 7.94 (s, 1H), 8.16 (s, 1H), 9.00 (s, 1H), 9.99 (s, 1H). LCMS:The compound did not ionize well.

Intermediate 194:2-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2H-1,2,3-triazole-4-carbaldehyde

Intermediate 194A:1-(difluoromethyl)-4-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)pyridin-2(1H)-one

Intermediate 194A was prepared (0.20 g, 61.70%) as an of-white solid, byusing a similar synthetic protocol as that of Intermediate 42 andstarting from Intermediate 28A (0.13 g, 1.33 mmol) and Intermediate 58A(0.30 g, 1.33 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.62 (d, J=5.52 Hz,2H), 5.42 (s, 1H), 7.14 (d, J=2.01 Hz, 1H), 7.16-7.21 (m, 1H), 7.85-8.04(m, 1H), 8.07 (d, J=7.53 Hz, 1H), 8.91 (s, 1H). ¹⁹F NMR (400 MHz,DMSO-d₆) δ ppm −101.0. LCMS (Method-D): retention time 0.54 min,[M+H]243.0.

Intermediate 194

Intermediate 194 was prepared (0.08 g, 40.40%), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 194A (0.20 g, 0.82 mmol) and Dess-Martin periodinane (0.70g, 1.65 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.16-7.23 (m, 1H),7.24-7.27 (m, 1H), 7.70-8.07 (m, 1H), 8.12-8.18 (m, 1H), 9.76 (s, 1H),10.13 (s, 1H). LCMS (Method-J): retention time 0.98 min, [M+H] 241.0.

Intermediate195:1-(2-(difluoromethyl)pyrimidin-4-yl)-1H-imidazole-4-carbaldehyde

Intermediate 195A: 4-chloropyrimidine-2-carbaldehyde

To a stirred solution of 4-chloropyrimidine-2-carbonitrile (0.25 g, 1.79mmol) in THE (5 mL) was added 1M DIBAL-H in heptane (1.79 mL, 1.79 mmol)at −78° C. and the resulting reaction mixture was stirred at ambienttemperature for 3 h. The reaction mixture was diluted with a saturatedsolution of NH₄Cl (20 mL) and extracted with 10% MeOH in DCM (2×30 mL).The combined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure to obtainIntermediate 195A (0.100 g, crude). LCMS (Method-D): retention time 0.42min [M+H]143.2. The compound was taken directly to the subsequent stepwithout further purification or characterization.

Intermediate 195B: 4-chloro-2-(difluoromethyl)pyrimidine

Intermediate 195B was prepared (0.80 g, 36.70%), by using a similarsynthetic protocol as that of Intermediate 4B and starting fromIntermediate 195A (1.70 g, 11.93 mmol) and DAST (3.15 mL, 23.85 mmol).¹H NMR (300 MHz, CDCl₃) δ ppm 6.44-6.80 (m, 1H), 7.49 (d, J=5.40 Hz,1H), 8.76 (d, J=5.40 Hz, 1H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −118.95.The compound did not ionize well.

Intermediate 195

To a stirring solution of Intermediate 195B (0.01 g, 0.06 mmol) in1,4-Dioxane (5 mL) was added K₂CO₃ (0.02 g, 0.122 mmol) followed by1H-imidazole-4-carbaldehyde (0.01 g, 0.09 mmol) and the resultingreaction mixture was stirred at 80° C. for 12 h. The reaction mixturewas cooled to ambient temperature, filtered through Celite® and washedwith ethyl acetate (10 mL). The filtrate was evaporated under reducedpressure to obtain Intermediate 195 (0.005 g, 36.70%). LCMS (Method-D):retention time 0.92 min, [M+H]225.2. ¹H NMR (400 MHz, CDCl₃) δ ppm6.54-6.81 (m, 1H), 7.51 (m, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.58 (d, J=1.2Hz, 1H), 9.02 (d, J=5.6 Hz, 1H), 10.01 (s, 1H). ¹⁹F NMR (400 MHz,DMSO-d₆) δ ppm −119.25.

Intermediate 196: 4-(5-formyl-2H-tetrazol-2-yl)-2-methoxybenzonitrile

Intermediate 196A: ethyl2-(4-cyano-3-methoxyphenyl)-2H-tetrazole-5-carboxylate

Intermediate 196A was prepared (0.15 g, 7.71%) as a brown solid, byusing a similar synthetic protocol as that of Intermediate 191A andstarting from 4-amino-2-methoxybenzonitrile (1.00 g, 6.75 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.48-1.52 (t, J=6.80 Hz, 3H), 4.09 (s, 3H),4.56-4.62 (m, 2H), 7.79 (d, J 8.40 Hz, 1H), 7.85 (d, J=1.60 Hz, 1H),7.91-7.94 (m, 1H). LCMS (Method-1) retention time 1.60 min, [M+H] 274.2.

Intermediate 196B:4-(5-(hydroxymethyl)-2H-tetrazol-2-yl)-2-methoxybenzonitrile

Intermediate 196B was prepared (0.06 g, 54.50%), by using a similarsynthetic protocol as that of Intermediate 60B and starting Intermediate196A (0.13 g, 0.48 mmol) and NaBH₄ (0.07 g, 1.90 mmol). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 4.07 (s, 3H), 4.82 (d, J=7.20 Hz, 2H), 5.84 (t, J=8.00Hz, 1H), 7.80-7.86 (m, 2H), 8.06 (m, 1H). LCMS (Method-1) retention time1.52 min, [M+H] 232.2.

Intermediate 196

Intermediate 196 was prepared (0.95 g, crude), by using a similarsynthetic protocol as that of Intermediate 9 and starting fromIntermediate 196B (0.10 g, 0.43 mmol) and Dess-Martin periodinane (0.37g, 0.86 mmol). LCMS (Method-1): retention time 1.29 min, [M−H] 228.2.The compound was taken directly to the subsequent step without furtherpurification or characterization.

Intermediate 197:(1-(5-cyano-4-methoxypyridin-2-yl)-3-methyl-2-oxoimidazolidin-4-yl)methylmethanesulfonate

Intermediate 197A:6-(4-(hydroxymethyl)-3-methyl-2-oxoimidazolidin-1-yl)-4-methoxynicotinonitrile

A solution of Intermediate 93C (0.50 g, 1.92 mmol) in ethyl acetate (20mL) was purged with nitrogen for 2 minutes. 10% Pd/C (0.10 g, 0.96 mmol)was added and reaction mixture was stirred at ambient temperature for 20h under H₂ atmosphere. The reaction mixture was filtered through Celite®and filtrate was concentrated under vacuum to obtain Intermediate 197A(0.25 g, 47.10%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.83 (s, 3H), 3.46-3.53 (m, 1H), 3.62-3.73 (m, 2H), 3.79 (dd, J=10.79,5.27 Hz, 1H), 3.93 (s, 3H), 3.97-4.04 (m, 1H), 4.98 (t, J=5.52 Hz, 1H),8.06 (s, 1H), 8.54 (s, 1H). LCMS (Method-D): retention time 1.22 min,[M+H] 263.2.

Intermediate 197

Intermediate 197 was prepared (0.24 g, 81.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 59 andstarting from Intermediate 197A (0.20 g, 0.76 mmol) and mesyl chloride(0.07 mL, 0.91 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.87 (s, 3H), 3.24(s, 3H), 3.80 (dd, J=10.79, 4.77 Hz, 1H), 3.94 (s, 3H), 4.02-4.09 (m,1H), 4.10-4.16 (m, 1H), 4.36 (dd, J=11.04, 3.51 Hz, 1H), 4.50 (dd,J=11.04, 3.01 Hz, 1H), 8.04 (s, 1H), 8.56 (s, 1H). LCMS (Method-D):retention time 1.69 min, [M+H] 340.9.

Intermediate 198:1-methyl-5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3-dihydro-2H-imidazol-2-oneTFA Salt

Intermediate 198A: 1-(tert-butyl) 4-methyl3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1,4-dicarboxylate

To a stirred solution of methyl2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (5.00 g, 35.20 mmol) inMeCN (25 mL) was added K₂CO₃ (4.86 g, 35.20 mmol) followed by BOC₂O(8.17 mL, 35.2 mmol) at 0° C. and the resulting reaction mixture wasstirred at ambient temperature for 14 h. The reaction mixture wasdiluted with MeCN (50 mL) and K₂CO₃ (14.55 g, 105.00 mmol), iodomethane(6.58 mL, 105.00 mmol) was added and the resulting reaction mixture wasstirred at ambient temperature for additional 14 h. The reaction mixturewas filtered through Celite® and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography(Redisep-40 g, 10-20% EtOAc/n-hexane) to obtain Intermediate 198A (3.70g, 41.10%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (s,9H), 3.30 (s, 3H), 3.79 (s, 3H), 7.40 (s, 1H). LCMS (Method-O):retention time 1.17 min, [M−55] 201.2.

Intermediate 198B: methyl3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate TFA Salt

To a stirred solution of Intermediate 198A (3.70 g, 14.44 mmol) in DCM(20 mL) at 0° C. was added TFA (10 mL, 130 mmol) and the resultingmixture was stirred at ambient temperature for 2 h. The reaction mixturewas concentrated under reduced pressure. The residue was desolved indiethyl ether (50 mL) and the solid precipitate was filtered and driedunder vacuum to obtain Intermediate 198B (0.22 g, 98.00%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.30 (s, 3H), 3.37 (s, 3H), 5.33 (br. s., 1H), 7.38(s, 1H), 10.96 (br. s., 1H). LCMS (Method-O): retention time 0.16 min,[M+H] 156.9

Intermediate 198C: methyl3-methyl-2-oxo-1-trityl-2,3-dihydro-1H-imidazole-4-carboxylate

Intermediate 198C was prepared (2.90 g, 56.80%) as a white solid, byusing a similar synthetic protocol as that of Intermediate 75A andstarting from Intermediate 198B (2.00 g, 12.81 mmol) and trityl chloride(4.29 g, 15.37 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.27 (s, 3H), 3.69(s, 3H), 7.11-7.40 (m, 16H). LCMS (Method-D): retention time 3.28 min,[M+H] 399.2.

Intermediate 198_(D):4-(hydroxymethyl)-3-methyl-1-trityl-1,3-dihydro-2H-imidazol-2-one

To a stirred solution of Intermediate 198C (5.00 g, 12.55 mmol) in THE(40 mL) was added 2M solution of LiBH₄ in THE (18.82 mL, 37.6 mmol) at0° C. and the resulting reaction mixture was stirred at ambienttemperature for 14 h. The reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby column chromatography (Redisep-40 g, 50-80% EtOAc/n-hexane) to obtainIntermediate 198D (3.30 g, 71.00%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.06 (s, 3H), 4.21 (d, J 6.80, 2 H), 5.03 (t, J 14.00,1H), 6.07 (s, 1H), 7.09-7.17 (m, 6H), 7.22-7.37 (m, 9H). LCMS(Method-D): retention time 2.42 min, [M+H] 371.2.

Intermediate 198E:(3-methyl-2-oxo-1-trityl-2,3-dihydro-1H-imidazol-4-yl)methylmethanesulfonate

Intermediate 198E was prepared (1.40 g 99.17%), by using a similarsynthetic protocol as that of Intermediate 59 and starting fromIntermediate 198D (2.00 g, 5.40 mmol) and mesyl-C1 (0.50 mL, 6.48 mmol).¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.04-3.13 (s, 3H), 3.16-3.28 (s, 3H),4.38 (s, 2H), 6.67 (s, 1H), 7.20-7.38 (m, 15H). LCMS: The compound didnot ionize well.

Intermediate 198F-I:3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1-trityl-1,3-dihydro-2H-imidazol-2-one

To a stirred solution o Intermediate 51-I 0.50 g, 2.02 mmol) in MeCN (40mL) was added Intermediate 198E (0.70 g, 1.56 mmol), sodium iodide(0.234 g, 1.561 mmol), K₂CO₃ (0.647 g, 4.68 mmol) followed by4-methyl-1H-imidazole (0.18 g, 2.21 mmol) and the resulting mixture washeated at 65° C. for 4 h. The reaction mixture was cooled to ambienttemperature, filtered through Celite® and the filtrate was evaporatedunder reduced pressure. The residue was purified by columnchromatography (Redisep-40 g, 5-10% MeOH/CHCl₃) to obtain Intermediate198F-I (0.30 g, 32.10%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.98-1.11 (m,3H), 2.16-2.28 (m, 3H), 2.34-2.47 (m, 1H), 2.54-2.62 (m, 2H), 2.63-2.79(m, 3H), 2.87 (br. s., 1H), 3.09 (s, 3H), 3.17-3.30 (m, 1H), 4.04 (d, J14.00, 1H), 5.42 (s, 2H), 6.06 (s, 1H), 7.10-7.32 (m, 15H), 7.67 (d, J10.80, 1 H), 7.80 (d, J 10.40, 1H). LCMS (Method-O): retention time 1.87min, [M+H] 599.3.

Intermediate 198-I

Intermediate 198-I was prepared (0.55 g 93.20%), by using a similarsynthetic protocol as that of Intermediate 198B and starting fromIntermediate 198F-I (1.00 g, 1.67 mmol) and TFA (5 mL, 64.90 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28 (d, J 3.00, 3H), 2.17-2.45 (m, 3H),2.96-3.26 (m, 5H), 3.27-3.44 (m, 5H), 4.70 (br.s., 1H), 5.39-5.53 (m,2H), 6.32 (s, 1H), 7.29-7.33 (m, 1H), 7.79-7.91 (m, 2H), 8.49-8.84 (m,1H), (1 Exchangeable proton not observed). LCMS (Method-O): retentiontime 0.57 min, [M+H] 357.1.

Example 266-I:3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1-(2-methylpyridin-4-yl)-1,3-dihydro-2H-imidazol-2-one

Example 266-I was prepared (0.02 g, 18.73%), by using a similarsynthetic protocol as that of Intermediate 15C and starting fromIntermediate 198-I (0.08 g, 0.23 mmol) and 4-bromo-2-methylpyridine(0.05 g, 0.27 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (d, J=4.90 Hz,3H), 1.75 (br. s., 2H), 2.27 (s, 3H), 2.46 (s, 3H), 2.87 (br. s., 2H),2.98 (br.s., 1H), 3.28 (s, 2H), 3.33 (s, 3H), 4.18 (br.s., 1H),5.52-5.29 (m, 2H), 7.18 (s, 1H), 7.78-7.54 (m, 3H), 7.82 (d, J=8.10 Hz,1H), 8.40 (d, J=5.40 Hz, 1H), (1 Exchangeable proton not observed).LCMS/HPLC (Method-R): retention time 0.83 min, [M+H] 448.3, purity:97.78%. (Method-S): retention time 1.34 min, [M+H] 448.3, purity:97.09%. Chiral purity (Method-XVIII): retention time 13.72 min, 95.00%ee.

The examples in Table 4 were synthesized using procedures of Example 1-Ito 24-I, 81-I to 84-I, 113-I to 123-I and 266-I

HPLC/ LCMS Method: Ex- LCMS RT am- (M + (min.), ple Structure Name H)⁺Purity NMR 267-I

6-(5-((3,3-dimethyl- 5-(4-methyl-1-oxo- 1,3-dihydroiso- benzofuran-5-yl)piperazin-1- yl)methyl)-1,3,4- oxadiazol-2-yl)-4- methyl-nicotinonitrile (Enantiomer-I) 459.3 R: 1.20, 100% S: 1.62, 100% ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.07 (s, 3H), 1.30 (s, 3H), 1.89-1.99 (m, 1H),2.06 (d, J = 10.00 Hz, 1H), 2.31 (s, 3H), 2.63 (s, 4H), 2.95 (d, J =10.00 Hz, 1H), 3.99 (s, 2H), 4.40 (d, J = 8.10 Hz, 1H), 5.39 (s, 2H),7.66 (d, J = 8.10 Hz, 1H), 7.78 (d, J = 8.10 Hz, 1H), 8.32 (s, 1H), 9.12(s, 1H), (1 Exchangeable proton not observed). 268-I

6-(5-((3,3-dimethyl-5- (4-methyl-1-oxo-1,3- dihydroiso- benzofuran-5-yl)piperazin-1- yl)methyl)isoxazol-3- yl)-4- methyl- nicotinonitrile(Enantiomer-I) 458.2 R: 1.46, 100% S: 1.98, 100% XV: 8.87, 100% ee ¹HNMR (400 MHz, DMSO-d₆) δ ppm (s, 3H), 1.32 (s, 3H), 1.88 (t, J = 10.60Hz, 1H), 1.97 (d, J = 10.30 Hz, 1H), 2.26-2.33 (m, 3H), 2.54-2.65 (m,4H), 2.88 (d, J = 9.50 Hz, 1H), 3.84 (s, 2H), 4.40 (d, J = 8.10 Hz, 1H),5.37 (s, 2H), 6.96 (s, 1H), 7.64 (d, J = 8.10 Hz, 1H), 7.77 (d, J = 8.10Hz, 1H), 8.14 (s, 1H), 9.04 (s, 1H), (1 Exchangeable proton notobserved). 269-I

4-methoxy-6-(5- (((3S,5R)-3- methyl-5- (4-methyl-1-oxo-1,3- dihydroiso-benzofuran- 5-yl)piperazin-1- yl)methyl) isoxazol-3- yl)nicotinonitrile460.3 R: 1.30, 96.82% S: 1.67, 96.12% VIII: 6.79, 100% ee ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.03 (d, J = 6.10 Hz, 3H), 1.74-1.94 (m, 2H), 2.29(s, 3H), 2.83 (br. s., 2H), 2.99 (br. s., 1H), 3.86 (s, 2H), 4.12 (s,3H), 4.18 (d, J = 7.60 Hz, 1H), 5.39 (s, 2H), 7.01 (s, 1H), 7.66 (d, J =8.10 Hz, 1H), 7.89-7.72-7.89 (m, 2H), 8.94 (s, 1H), (1 Exchangeableproton not observed). 270-I

1-(difluoromethyl)-4- (4-(((3S,5R)-3- methyl- 5-(4-methyl-1-oxo- 1,3-dihydroiso- benzofuran- 5-yl)piperazin-1- yl)methyl)-2H-1,2,3-triazol-2-yl)pyridin- 2(1H)-one 471.1 R: 1.10, 100% S: 1.55, 100% XXIX:3.35, 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (s, 1H), 8.02 (d, J =7.80 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J = 8.10 Hz, 1H), 7.66 (d, J = 7.80Hz, 1H), 7.10 (dd, J = 7.90, 2.30 Hz, 1H), 6.88 (d, J = 2.20 Hz, 1H),5.47-5.27 (m, 2H), 4.18 (d, J = 8.30 Hz, 1H), 3.76 (s, 2H), 2.98 (br.s., 1H), 2.81 (d, J = 9.80 Hz, 2H), 2.33 3 (s, 3H), 1.8 (d, J = 9.00 Hz,2H), 1.03 (d, J = 6.10 Hz, 3H), (1 Exchangeable proton not observed).¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm-103.0. 271-I

5-((2R,6S)-4- ((1-(2- (difluoromethyl) pyrimidin-4-yl)- 1H- imidazol-4-yl)methyl)-6- methylpiperazin- 2-yl)- 4- methyl- isobenzofuran-1(3H)-one 455.3 S: 1.31, 100% R: 0.98, 100% VIII: 3.83, 100% ee ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.02 (d, J = 6.10 Hz, 3H), 1.80 (q, J = 10.00Hz, 2H), 2.31-2.18 (m, 3H), 2.91-2.69 (m, 2H), 2.96 (br. s., 1H), 3.51(s, 2H), 4.16 (d, J = 9.00 Hz, 1H), 5.49-5.26 (m, 2H), 6.97 (s, 1H),7.64 (d, J = 7.80 Hz, 1H), 7.79 (d, J = 7.80 Hz, 1H), 7.91 (s, 1H), 8.08(d, J = 5.60 Hz, 1H), 8.65 (s, 1H), 9.05 (d, J = 5.60 Hz, 1H), (1Exchangeable proton not observed). ¹⁹F NMR (400 MHz, DMSO-d₆) δ-119.33272-I

4-(5-(((3R,4T)-4- hydroxy-3- (4-methyl- 1-oxo-1,3- dihydroiso-benzofuran- 5-yl)piperidin-1- yl)methyl)-2H- tetrazol-2-yl)-2- methoxy-benzonitrile 461.2 S: 1.60, 100% R: 1.22, 100% ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.68-1.56 (m, 1H), 1.99-1.85 (m, 2H), 2.31- 2.19 (m, 4H),2.41-2.31 (m, 1H), 2.85 (d, J = 10.80 Hz, 1H), 2.98 (d, J = 10.80 Hz,1H), 3.13- 3.04 (m, 1H), 3.17 (s, 1H), 3.72 (br. s., 1H), 3.98 (s, 3H),4.59 (d, J = 5.40 Hz, 1H), 5.47-5.28 (m, 2H), 7.54 (d, J = 7.80 Hz, 1H),7.63 (d, J = 8.10 Hz, 1H), 7.80 (d, J = 8.30 Hz, 1H), 7.85 (s, 1H), 8.04(d, J = 8.60 Hz, 1H). 273-I

6-(5-((3- (difluoromethyl)-5-(4- methyl-1-oxo-1,3- dihydroiso-benzofuran- 5-yl)piperazin-1- yl)methyl)-1,3,4- oxadiazol-2-yl)-4-methylnicotinonitrile (Enantiomer-I) 481.2 S: 1.67, 100% R: 1.27, 100%¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.02 (t, J = 10.50 Hz, 1H), 2.33-2.15(m, 4H), 2.63 (s, 3H), 2.88 (br. s., 1H), 2.95 (d, J = 10.80 Hz, 1H),3.02 (d, J = 9.00 Hz, 1H), 3.31 (br. s., 1H), 4.10 (s, 2H), 4.24 (d, J =9.80 Hz, 1H), 5.45- 5.37 (m, 2H), 5.96 (d, J = 4.40 Hz, 1H), 7.68 (d, J= 8.10 Hz, 1H), 7.78 (d, J = 8.10 Hz, 1H), 8.33 (s, 1H), 9.12 (s, 1H)274-I

4-methoxy-6-(3- methyl-4-(((3S,5R)-3- methyl-5-(4-methyl-1- oxo-1,3-dihydroiso- benzofuran- 5-yl)piperazin-1- yl)methyl)-2-oxoimidazolidin-1- yl)nicotinonitrile (Diastereomer-I) 491.2 P: 8.11,99.10% Q: 7.37, 99.30% XXXIII: 14.00, 100% ee ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.02 (d, J = 6.53 Hz, 3H), 1.75-1.84 (m, 2H), 2.28 (s, 3H),2.60-2.66 (m, 2H), 2.82 (d, J = 10.54 Hz, 2H), 2.86-2.93 (m, 4H), 3.78(dd, J = 10.79, 5.27 Hz, 1H), 3.85-3.92 (m, 1H), 3.94 (s, 3H), 4.02-4.14(m, 2H), 5.40 (s, 2H), 7.67 (d, J = 8.03 Hz, 1H), 7.82 (d, J = 8.03 Hz,1H), 8.06 (s, 1H), 8.56 (s, 1H) (1 Exchangeable proton not observed).275-I

1-(2-methoxypyridin- 4-yl)-3-methyl-4- (((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3- dihydroiso- benzofuran- 5-yl)piperazin-1-yl)methyl)-1,3- dihydro-2H-imidazol- 2-one 464.3 R: 1.00, 96.14% S:1.50, 97.76% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (br. s., 3H), 2.27 (s,3H), 2.85 (br. s., 3H), 2.95 (br. s., 3H), 3.28 (s, 2H), 3.32 (s, 3H),3.86 (s, 3H), 4.14 (br. s., 1H), 5.38 (s, 2H), 7.19 (s, 1 H), 7.34 (d, J= 1.70 Hz, 1H), 7.50 (dd, J = 5.90, 2.00 Hz, 1H), 7.68 (d, J = 7.30 Hz,1H), 7.82 (d, J = 7.80 Hz, 1H), 8.14 (d, J = 5.90 Hz, 1H). 276-I

1-(2- (difluoromethyl) pyridin- 4-yl)-3-methyl-4- (((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3- dihydroisobenzofuran- 5-yl)piperazin-1-yl)methyl)-1,3- dihydro-2H-imidazol- 2-one 484.3 R: 1.14, 98.10% S:1.52, 96.63% XV: 8.55 100% ee ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (d, J= 5.10 Hz, 3H), 1.72 (br. s., 2H), 2.27 (s, 3H), 2.86 (br. s., 2H), 2.96(br. s., 1H), 3.33 (s, 3H), 3.30 (s, 3H), 4.14 (br. s., 1H), 5.46-5.27(m, 2H), 6.95 (s, 1H), 7.33 (s, 1H), 7.68 (d, J = 8.10 Hz, 1H), 7.82 (d,J = 8.10 Hz, 1H), 8.00 (d, J = 4.60 Hz, 1H), 8.29 (s, 1H), 8.65 (d, J =5.60 Hz, 1H)

Intermediate 199-I:4-methyl-5-((2R,6S)-6-methylpiperazin-2-yl)isobenzofuran-1(3H)-one-3,3-d2TFA Salt

Intermediate 199A-I: tert-butyl(3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl-3-d)piperazine-1-carboxylate

To a stirred solution of Intermediate 51-I (1.50 g, 4.33 mmol) in THE(150 mL) was added 1M LiHMDS in THE (21.65 mL, 21.65 mmol) and thereaction mixture was stirred at ambient temperature for 30 minutes. Tothe resulting reaction mixture was added D₂O (5.09 mL, 281 mmol) andstirring at ambient temperature was continued for 15 minutes. Thereaction mixture was diluted with water (100 mL) and extracted withethyl acetate (2×100 mL). The combined organic layers were washed withbrine (50 mL), dried over anhydrous sodium sulfate and evaporated underreduced pressure. The residue was purified by column chromatography(Redisep-40 g, 60-80% EtOAc/n-hexane) to obtain Intermediate 199A-I(1.00 g, 33.20%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.05(s, 3H), 1.42 (s, 9H), 2.32 (s, 3H), 2.42 (br s, 1H), 2.70-2.88 (m, 2H),3.91-4.04 (m, 3H), 5.37-5.44 (m, 1H), 7.69 (d, J=7.90 Hz, 1H), 7.82 (d,J=7.90 Hz, 1H), (1 Exchangeable proton not observed). LCMS (Method-D):retention time 2.46 min, [M+H] 348.2.

Intermediate 199B-I and 199C-I: tert-butyl(3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl-3,3-d2)piperazine-1-carboxylate

Intermediate 199B-I was prepared (0.40 g, 39.80%) as a white solid, byusing a similar synthetic protocol as that of Intermediate 199A-I andstarting from Intermediate 199A-I (1.00 g, 2.89 mmol) and 1M LHMDS(14.39 mL, 14.39 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.05 (s, 3H),1.42 (s, 9H), 2.32 (s, 3H), 2.42 (br s, 1H), 2.70-2.88 (m, 2H),3.91-4.04 (m, 3H), 7.69 (d, J=7.90 Hz, 1H), 7.82 (d, J=7.90 Hz, 1H), (1exchangeable proton not observed). LCMS (Method-D): retention time 2.47min, [M+H] 349.2. The isotopic ratio of mono-D and di-D (28:72) wasdetermined by ¹H NMR.

Intermediate 199C-I was prepared (0.20 g, 19.88%) as a white solid, byusing a similar synthetic protocol as that of Intermediate 199A andstarting from Intermediate I99B-I (0.40 g, 1.15 mmol) and 1M LiHMDS(5.76 mL, 5.76 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.05 (s, 3H), 1.42(s, 9H), 2.32 (s, 3H), 2.42 (br., s., 1H), 2.70-2.88 (m, 2H), 3.91-4.04(m, 3H), 7.69 (d, J=7.90 Hz, 1H), 7.82 (d, J=7.90 Hz, 1H), (1exchangeable proton not observed). LCMS (Method-D): retention time 2.47min, [M+H] 349.2. The isotopic ratio of mono-D and di-D (17:83) wasdetermined by ¹H NMR.

Intermediate 199-I

Intermediate 199-I was prepared (0.18 g, 87.00%) as a pale yellow solid,by using a similar synthetic protocol as that of Intermediate 198B andstarting from Intermediate 199C-I (0.20 g, 0.57 mmol) and TFA (0.88 mL,11.48 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm ¹H NMR (400 MHz, DMSO-d₆) δppm 1.29 (d, J=6.00 Hz, 3H), 2.38 (s, 3H), 3.0-3.20 (m, 2H), 3.55-3.68(m, 3H), 4.86 (br., s., 1H), 7.88-7.82 (m, 2H), (2 Exchangeable protonnot observed). LCMS (Method-J): retention time 0.40 min, [M+H] 249.2.

Intermediate 200-I:4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl-3-d)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile

To a stirred solution of Example 83-I (0.10 g, 0.22 mmol) in THE (10 mL)at −50° C. was added 1M LiHMDS in THE (1.13 mL, 1.13 mmol) and thereaction mixture was stirred at same temperature for 10 minutes. To theresulting reaction mixture was added D₂O (2.0 mL, 113 mmol) and stirringat −50° C. was continued for 10 minutes. The reaction mixture wasdiluted with water (15 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine (10 mL), dried overanhydrous sodium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography (Redisep-24 g, 3-4%MeOH/DCM) to obtain

Intermediate 200-I (0.045 g, 40.00%) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.02 (d, J=5.60 Hz, 3H), 1.75 (m, 2H), 2.27 (s, 3H),2.38-2.41 (m, 2H), 2.71 (s, 3H), 2.75-2.86 (m, 2H), 3.76 (s, 2H),4.05-4.29 (m, 1H), 5.34-5.37 (m, 1H), 7.50 (d, J=8.00 Hz, 1H), 7.80 (d,J=8.00 Hz, 1H), 8.07-8.26 (m, 2H), 8.87-9.03 (m, 1H). LCMS (Method-D):retention time 1.15 min, [M+H] 445.0. The isotopic ratio of mono-D anddi-D (27:73) was determined by ¹H NMR.

Example 277-I:4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl-3,3-d2)piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile

Example 277-I was prepared (0.01 g, 14.80%) as a white solid by using asimilar synthetic protocol as that of Intermediate 96-I and startingfrom Intermediate 199-I (0.05 g, 0.188 mmol) and Intermediate 28 (0.04g, 0.188 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=5.60 Hz, 3H),1.75-1.88 (m, 2H), 2.26 (s, 3H), 2.61 (s, 3H), 2.74-2.86 (m, 2H),2.92-3.04 (m, 1H), 3.76 (s, 2H), 4.14-4.18 (m, 1H), 7.65 (d, J=7.60 Hz,1H), 7.79 (d, J=8.10 Hz, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.92 (s, 1H),(1 Exchangeable proton not observed). HPLC (Method-P): retention time7.71 min, purity: 98.20%, (Method-Q): retention time 5.65 min, purity:98.17%. LCMS (Method D): retention time 1.93 min, [M+H]446.2. Theisotopic ratio of mono-D and di-D (17:83) was determined by ¹H NMR.

Alternative Procedure for Example 277-I

Example 277-I was prepared (0.001 g, 2.82%) as a white solid by using asimilar synthetic protocol as that of Intermediate 199A-I and startingfrom Intermediate 200-I (0.04 g, 0.101 mmol) and 1M LiHMDS (0.50 mL,0.50 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (d, J=5.60 Hz, 3H),1.75-1.88 (m, 2H), 2.26 (s, 3H), 2.61 (s, 3H), 2.74-2.86 (m, 2H),2.92-3.04 (m, 1H), 3.76 (s, 2H), 4.14-4.18 (m, 1H), 7.65 (d, J=7.60 Hz,1H), 7.79 (d, J=8.10 Hz, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.92 (s, 1H),(1 Exchangeable proton not observed). HPLC (Method-P): retention time7.49 min, purity: 92.50%, (Method-Q): retention time 6.54 min, purity:93.04%. LCMS (Method-D): retention time 1.84 min, [M+H]446.2. Chiralpurity (Method-VII): retention time 4.99 min, 100% ee. The isotopicratio of mono-D and di-D (5:95) was determined by ¹H NMR.

The examples in Table 5 were synthesized using procedures of Example 1-Ito 24-I, 81-I to 84-I, 113-I to 123-I, 266-I and 277-I

HPLC/ LCMS Method: Ex- LCMS RT am- (M + (min.), ple Structure Name H)⁺Purity NMR 278-I

4-methyl-6-(4-(((3S,5R)-3- methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl-3,3-d2)piperazin-1-yl)methyl)-1H-pyrazol-1- yl)nicotinonitrile (Isotopic ratio of mono-Dand di-D: 17:83) 445.2 P: 4.83, 96.00% Q: 6.29, 97.80% ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.00 (d, J = 6.00 Hz, 3H), 1.69 (br., s., 2H), 2.12 (s,3H), 2.56 (s, 3H), 2.77 (d, J = 9.50 Hz, 2H), 2.94 (s, 1H), 3.50 (s,2H), 4.13 (d, J = 8.50 Hz, 1H), 7.62 (d, J = 7.50 Hz, 1H), 7.70- 7.89(m, 2H), 7.96 (s, 1H), 8.50 (s, 1H), 8.81 (s, 1H), (1 Exchangeableproton not observed). 279-I

4-methyl-6-(4-(((3S,5R)-3- methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl-3,3-d2)piperazin-1- yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile (Isotopic ratio of mono-D and di-D: 17:83)446.2 P: 8.22, 97.00% Q: 9.50, 96.30% ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.01 (d, J = 6.00 Hz, 3H), 1.66-1.87 (m, 2H), 2.25 (s, 3H), 2.56 (s,3H), 2.82 (t, J = 8.80 Hz, 2H), 2.95 (br., s., 1H), 3.73 (s, 2H), 4.14(d, J = 7.50 Hz, 1H), 7.64 (d, J = 8.00 Hz, 1H), 7.78 (d, J = 8.00 Hz,1H), 8.27 (s, 1H), 8.76 (s, 1H), 8.98 (s, 1H), (1 Exchangeable protonnot observed). 280-I

4-methyl-6-(5-(((3S,5R)-3- methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl-3,3-d2)piperazin-1- yl)methyl)-1,3,4-oxadiazol-2- yl)nicotinonitrile (Isotopic ratio of mono-D and di-D:22:78) 447.2 T: 5.26, 94.27% S: 12.13, 95.10% ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.03 (d, J = 6.50 Hz, 3H), 1.84-2.08 (m, 2H), 2.28 (s, 3H),2.80-3.94 (m, 3H), 3.99 (s, 3H), 4.18 (d, J = 8.00 Hz, 3H), 7.50 (d, J =8.00 Hz, 1H), 7.85 (d, J = 8.00 Hz, 1H), 8.33 (s, 1H), 9.12 (s, 1H), (1Exchangeable proton not observed). 281-I

4-methoxy-6-(5-(((3S,5R)- 3-methyl-5-(4-methyl-1- oxo-1,3-dihydroisobenzofuran-5- yl-3,3-d2)piperazin-1- yl)methyl)isoxazol-3-yl)nicotinonitrile (Isotopic ratio of mono-D and di-D: 22:78) 462.2 P:4.53, 90.04% R: 5.64, 90.00% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J= 6.50 Hz, 3H), 1.75-1.85 (m, 2H), 2.25 (s, 3H), 2.81-2.90 (m, 2H),2.95-3.0 (m, 1H), 3.85 (s, 2H), 4.01-4.23 (m, 4H), 7.01 (s, 1H), 7.66 (d, J = 8.00 Hz, 1H), 7.73- 7.85 (m, 2H), 8.94 (s, 1H), (1 Exchangeableproton not observed).

BIOLOGICAL ASSAYS

The pharmacological properties of the compounds of this invention may beconfirmed by a number of biological assays. The exemplified biologicalassays, which follow, have been carried out with compounds of theinvention.

When more than one data point has been generated for any particular testfor a particular compound, it is represented as an average in the table.

Thallium Flux Assay

Solutions and reagents: Thallium flux assay was performed using FluxORkit (F10017, Life Technologies). Loading buffer, assay buffer andstimulus buffer were prepared using kit components. HBSS (Hank'sbalanced salt solution, Cat #14025-092) was purchased separately fromLife Technologies.

To prepare 10 ml of loading buffer: 10 μl of FluxOR dye (reconstitutedin DMSO) was first added to 100 μl of powerload concentrate and this mixalong with 100 μl of Probenicid (100×) was then added to 9.79 ml ofHBSS. Assay buffer (10 ml) was prepared by addition of 2 ml of FluxORchloride free buffer (5×), 100 μl of Probenicid (100×), and 0.2 ml ofOuabain (13.77 mM) to 7.7 ml of deionized water. Stimulus buffer wascomposed of 15 mM Tl₂SO₄, 0.75 mM K₂SO₄ in FluxOR chloride free buffer(diluted to 1× using deionized water). The final concentration of Tl₂SO₄and K₂SO₄ in the assay plate was 3 mM and 0.15 mM, respectively.

Plating and induction of cells: The CHO T-Rex hROMK (human K_(ir)1.1)stable cell line was maintained in Ham's F12 media supplemented with 10%FBS, 1% Penicillin-Streptomycin, 500 μg/ml Zeocin and 10 μg/mlBlasticidin at 37° C. in a 5% CO₂ incubator. One day before theexperiment, the cells were dissociated by incubation with Versenesolution (15040-066, Life Technologies) for 10 minutes at 37° C.followed by addition of growth media. The cell suspension wascentrifuged at 1200 rpm for 5 min. After discarding the supernatant, thecells were resuspended in fresh growth media and cell concentration wasdetermined using a hemocytometer. Next, 0.5 μg/ml of Doxycycline wasadded to the cell suspension to induce hROMK channel expression and 50μl (10,000 cells/well) of cell suspension was added to each well of apoly-D lysine coated 384 well black, optically clear bottom plate(6007718, Perkin Elmer). The assay plate was kept at 37° C. in a 5% CO₂incubator.

Assay protocol: On the day of experiment, media was removed and loadingbuffer was added (30 μl/well) to the assay plate. The cells wereincubated in the loading buffer for 30 minutes at 37° C. The loadingbuffer was then replaced by assay buffer (30 μl/well) followed byaddition of test compounds or controls. The cells were incubated withcompounds for 30 minutes and the plate was then mounted on FlexStation(Molecular Devices) for fluorescence read out with excitation andemission wavelengths at 488 and 525 nm, respectively. Each well was readfor 90 sec at 2 sec interval and the stimulus buffer was added after 20seconds of baseline recording. The final DMSO concentration was either0.5 or 1% in the assay plate. Positive and negative controls weredefined by addition of DMSO or 3 μM of a standard ROMK inhibitor,respectively, to the wells instead of a test compound.

Data analysis: The slope (over a period of 15 seconds) of fluorescenceincrease after stimulus buffer addition was exported from SoftMax Prointo a custom made software where it was converted to % inhibition. A10-point concentration response curve was used to estimate the IC₅₀value of test compounds.

The data in Table 6 is reported with two significant figures.

TABLE 6 Patent Example Human ROMK Th Number Flux IC50 (nM)  1-I 14  2-I15  3-I 210 4 640 5 270  6-I 40  7-I 1000  8-I 280  9-I 44  10-I 620 11-I 30  12-I 530  13-I 110  14-I 36  15-I 84  16-I 33  17-I 900  18-I870  19-I 180  20-I 490  21-I 93  22-I 26  23-I 30  24-I 500    1-II 800 25-I 51  26-I 69  27-I 32  28-I 85  29-I 120  30-I 260  31-I 190  32-I24  33-I 690  34-I 190  35-I 120  36-I 680  37-I 16  38-I 3400  39-I 770 40-I 27  41-I 980  42-I 490  43-I 110  44-I 200  45-I 370  46-I 26 47-I 49  48-I 62  49-I 23  50-I 670  51-I 29  52-I 2.8  53-I 370   2-II 1200  54-I 110  55-I 86  56-I 150  57-I 59  58-I 60  59-I 20 61-I 57  62-I 170  63-I 60  64-I 8.8  65-I 14  66-I 33  67-I 110  68-I1700  69-I 900  70-I 59  71-I 800  72-I 550  73-I 150  74-I 570  75-I680  76-I 300  77-I 820  78-I 810  79-I 320  80-I 490  81-I 22  82-I 13 83-I 23  84-I 52  85-I 45  86-I 64   87-III 62   88-III 36   89-III 30 90-I 49  91-I 56  92-I 35  93-I 44  94-I 39  95-I 26  96-I 27  97-I 28 98-I 45  99-I 33 100-I 40 101-I 26 102-I 48 103-I 25 104-I 36 105-I 26106-I 57 107-I 26 108-I 30 109-I 56 110-I 25 111-I 23 112-I 18 113-I 25114-I 32 115-I 23 116-I 39 117-I 34 118-I 290 119-I 140 120-I 160 121-I31 122-I 50 123-I 74 125-I 30 126-I 34 127-I 21 128-I 66 129-I 26 130-I52 131-I 75 132-I 170 133-I 84 134-I 43 135-I 170 136-I 28 137-I 26138-I 670 139-I 36 140-I 26 141-I 69 142-I 76 143-I 63 144-I 24 145-I 15146-I 25 147-I 87 148-I 27 149-I 52 150-I 100 151-I 43 152-I 490 153-I84 154-I 12 155-I 11 156-I 14 157-I 12 158-I 36 159-I 16 160-I 130 161-I170 162-I 260 163-I 29 164-I 31 165-I 67 166-I 30 167-I 26 168-I 20169-I 23 170-I 39 171-I 27 172-I 160 173-I 55 174-I 220 175-I 31 176-I120 177-I 500 178-I 220 179-I 360 180-I 77 181-I 150 182-I 260 183-I 180184-I 30 185-I 100 186-I 18 187-I 43 188-I 37 189-I 25 190-I 17 191-I 29192-I 16 193-I 44 194-I 60 195-I 66 196-I 35 197-I 15 198-I 83  199-IV16  200-II 64 201-I 190 202-I 140 203-I 43 204-I 220 205-I 71 206-I 82207-I 53 208-I 190 209-I 100 210-I 41 211-I 30  212-II 97 213-I 1200214-I 6.6 215-I 11 216-I 25 217-I 24 218-I 33 219-I 21 220-I 29 221-I 22222-I 60 223-I 18 224-I 27 225-I 19 226-I 14 227-I 28 228-I 14 229-I 21230-I 32 231-I 240 232-I 480 233-I 22 234-I 78 235-I 83 236-I 75 237-I69 238-I 470 239-I 63 240-I 42 241-I 41 242-I 10 243-I 13  244-II 17245-I 18 246-I 870 247-I 330 248-I 1500 249-I 120 250-I 27 251-I 61252-I 72 253-I 400 254-I 1600 255-I 33  256-II 57 257-I 1400 258-I 250259-I 53 260-I 430  261-II 27 262-I 120 263-I 23 264-I 580 265-I 22266-I 36 267-I 16 268-I 20 269-I 24 270-I 580 271-I 100 272-I 65 273-I720 274-I 58 275-I 42 276-I 35 277-I 38

ROMK Manual Patch Clamp Assay

Cell culture conditions: Cells were maintained in conditions similar tothose for Thallium flux assay. hROMK channel expression was induced byadding 0.6 μg/ml of Doxycycline 16-24 hrs prior to the experiments. Onthe day of experiment, the cells were dissociated using Versene,resuspended in growth media and plated onto coverslips 15 minutes priorto use.

Electrophysiology: The coverslip plated with cells was placed in theexperiment chamber perfused with bath solution composed of (in mM): 135NaCl, 5 KCl, 2 CaCl₂), 1 MgCl₂, 10 HEPES, 5 Glucose (pH 7.4). Patchpipettes with resistance between 2-5 Megaohms, when filled with asolution containing (in mM): 135 KCl, 1 EGTA, 1 MgCl₂, 10 HEPES, 2Na₂ATP (pH 7.3), were used to form gigaseals. The cells were voltageclamped at −75 mV in whole-cell configuration using an Axopatch 200b orMulticlamp 700b (Molecular Devices) amplifier controlled by pClampSoftware (Molecular Devices). The current was recorded by applying avoltage step to −120 mV every 10 seconds. For each compound, 4-6concentrations were applied for 3-8 minutes in a successive mannerstarting with the lowest concentration. At the end of the experiment,the cells were perfused with bath solution containing 2 mM Ba²⁺ toisolate the contribution of hROMK current.

Data analysis: Raw current values (5 traces each for control, differentcompound concentration and Ba2+ treatment groups) were exported fromClampfit into Microsoft Excel where the current remaining afterapplication of Ba²⁺ was subtracted from raw current to obtain hROMKspecific current. These hROMK current values (average of 5 traces foreach group) were then imported into a custom made template to generate aconcentration response curve, which was subsequently fitted with a fourparameter equation to calculate the IC₅₀ value of the test compound.

The data in Table 7 is reported with two significant figures.

TABLE 7 Patent Example Number ROMK EP IC50 (nM)  1-I 11  2-I 5.7  3-I 44 14-I 51  16-I 11  22-I 25  23-I 4.9  37-I 22  59-I 4.8  61-I 40  65-I9.8  66-I 4.7  67-I 29  82-I 7.9  83-I 6.8  84-I 57   87-III 57  90-I 74 92-I 23  94-I 14  96-I 12  97-I 43  98-I 23  99-I 29 100-I 25 101-I 34102-I 17 103-I 29 105-I 11 106-I 10 107-I 18 108-I 21 109-I 54 110-I 16111-I 62 121-I 740 126-I 17 127-I 14 130-I 20 139-I 30 148-I 19 151-I 64164-I 30 165-I 39 166-I 13 167-I 18 168-I 29 171-I 26 173-I 21 175-I 17184-I 10 187-I 25 188-I 18 189-I 17 190-I 13 191-I 21 193-I 20 195-I 79207-I 18 210-I 20 216-I 14 221-I 13 228-I 20 230-I 19 240-I 34  244-II22 255-I 9.1 263-I 23 267-I 17hERG Manual Patch Clamp Assay

hERG electrophysiology assay: The experimental compounds were assessedfor hERG activity on HEK 293 cells stably expressing hERG channels usingpatch clamp technique. Coverslips plated with hERG expressing cells wereplaced in the experimental chamber and were perfused with a solutioncomposed of (in mM): 140 NaCl, 4 KCl, 1.8 CaCl₂), 1 MgCl₂, 10 Glucose,10 HEPES (pH 7.4, NaOH) at room temperature. Borosilicate patch pipetteshad tip resistances of 2-4 Mohms when filled with an internal solutioncontaining: 130 KCl, 1 MgCl₂, 1 CaCl₂), 10 EGTA, 10 HEPES, 5 ATP-K₂ (pH7.2, KOH). The cells were clamped at −80 mV in whole cell configurationusing an Axopatch 200B (Axon instruments, Union City, Calif.) patchclamp amplifier controlled by pClamp (Axon instruments) software. Uponformation of a gigaseal, the following voltage protocol was repeatedly(0.05 Hz) applied to record tail currents: depolarization step from −80mV to +20 mV for 2 seconds followed by a hyperpolarization step to −65mV (3 seconds) to elicit tail currents. Compounds were applied afterstabilization of tail current. First, tail currents were recorded inpresence of extracellular solution alone (control) and subsequently, inextracellular solution containing increasing compound concentrations.Each compound concentration was applied for 2-5 minutes. The percentageinhibition at each concentration was calculated as reduction in peaktail current with respect to the peak tail current recorded in thepresence of control solution. Data analysis was performed in a custommade template. The percent inhibitions at different concentrations wereplotted to obtain a concentration response curve, which was subsequentlyfitted with a four parameter equation to calculate hERG IC₅₀ value.

Some compounds of the present invention were tested in the hERG assay.Preferred compounds have low hERG inhibition or a high IC₅₀.

TABLE 8 Patent Example Number hERG EP % Inh @ 1 uM  1-I 26  2-I 19  3-I26  6-I 38  9-I 47  11-I 40  14-I 1.7  15-I 5.8  16-I 7.3  21-I 8.5 22-I 6.0  23-I 12  25-I 8.7  26-I 20  27-I 11  28-I 15  32-I 6.2  35-I20  37-I 6.2  40-I 54  46-I 43  47-I 49  48-I 78  49-I 27  51-I 43  52-I72  57-I 26  59-I 15  63-I 23  64-I 45  65-I 21  66-I 0  67-I 7.1  70-I8.4  81-I 7.7  82-I 7.1  83-I 11  84-I 6.7  85-I 11  86-I 8.8   87-III4.9   88-III 8.3   89-III 14  90-I 2.6  91-I 0  92-I 5.2  93-I 23  94-I4.3  95-I 13  96-I 9.6  98-I 9.3  99-I 9.6 100-I 3.6 101-I 3.0 102-I 5.6103-I 14 104-I 3.4 105-I 9.7 106-I 0.98 107-I 13 108-I 8.7 109-I 3.6110-I 9.2 111-I 5.1 112-I 22 114-I 4.2 115-I 45 116-I 6.4 121-I 10 122-I6.6 123-I 7.2 125-I 8.3 126-I 7.8 127-I 16 128-I 19 129-I 32 130-I 8.4134-I 22 136-I 29 137-I 23 139-I 6.6 140-I 49 141-I 7.1 142-I 8.5 143-I49 144-I 7.8 145-I 25 146-I 16 148-I 8.8 149-I 7.6 150-I 14 151-I 5.1153-I 10 154-I 43 155-I 26 156-I 51 157-I 40 158-I 20 159-I 21 163-I 4.5164-I 6.0 165-I 5.4 166-I 6.0 167-I 11 168-I 22 169-I 12 170-I 26 171-I16 173-I 4.0 175-I 15 184-I 6.1 185-I 9.6 187-I 11 188-I 18 189-I 8.9190-I 9.1 191-I 4.3 192-I 46 193-I 14 194-I 11 195-I 5.9 196-I 18 197-I75 198-I 0  199-IV 22  200-II 27 203-I 16 205-I 10 207-I 10 210-I 5.2211-I 58 214-I 22 215-I 29 216-I 5.6 217-I 16 218-I 39 219-I 75 220-I 30221-I 5.4 222-I 12 223-I 56 225-I 39 226-I 33 227-I 18 228-I 16 229-I 25230-I 2.2 233-I 31 236-I 20 237-I 37 239-I 18 240-I 8.3 241-I 18 242-I36 243-I 9.8 245-I 17 249-I 9.1 250-I 20 251-I 7.6 252-I 8.8 255-I 9.5 256-II 13 259-I 8.6  261-II 44 263-I 10 265-I 20 266-I 3.1 267-I 9.9268-I 9.0 269-I 9.5 272-I 5.2 274-I 43 275-I 8.4 276-I 5.4 277-I 7.0

What is claimed is:
 1. A compound having the structure of Formula (I)

or a salt thereof, wherein: R¹ is:

each W is independently NR^(1b) or O; Z is a bond or CHR^(1d); X isindependently N or CR^(1a), wherein X is N at only 0, 1, or 2 positions;each R^(1a) is independently H, F, Cl, —OH, —CN, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy, or C₁₋₃ fluoroalkoxy; eachR^(1b) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆ cycloalkylR^(1c) is independently H, deuterium, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, orC₃₋₆ cycloalkyl; R^(1d) is H, C₁₋₃ alkyl, C₁₋₄ fluoroalkyl, or C₃₋₆cycloalkyl; L¹ is —C(R)₂—, —C(O)—, or —C(R)₂—C(R)₂—; wherein R isindependently H, F, OH, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ alkoxyalkyl,or C₁₋₃ fluoroalkyl; wherein R is not —OH or F if it is attached to acarbon atom that is adjacent to a nitrogen atom: Ring B is phenyl,pyridinyl, pyrimidinyl, pyrrazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyrazinyl, oxazolyl, pyridazinyl, pyrrolidinyl, orimidazolidinyl; R² is a C₆₋₁₀ aryl, or a 5 to 10 membered heterocyclering containing 1 to 4 heteroatoms selected from N, O, and S, theheterocycle ring optionally containing an oxo substitution, the aryl orheterocycle ring are substituted with 0-3 R^(2a); R^(2a) isindependently OH, ═O, CN, halo, C₁₋₄ alkyl, C₁₋₄ deuteroalkyl, C₁₋₄fluoroalkyl, C₁₋₄ alkoxy, C₁₋₄ deuteroalkoxy, C₁₋₄ fluoroalkoxy, C₃₋₆cycloalkyl, C₃₋₆ cycloalkoxy, C(═O)NR^(4b)R^(4b), C(═O)CM alkyl,SO₂R^(e), NR^(4b)SO₂R^(4b), or a 4 to 6 membered heterocycle having 1,2, 3, or 4 heteroatoms selected from O, S, and N, the heterocycleoptionally containing an oxo substitution and is substituted with 0-3R^(2b); R^(2b) is independently C₁₋₃ alkyl, C₁₋₃ fluoralkyl, C₁₋₃hydroxyalkyl, C₃₋₆ cycloalkyl, or C₃₋₆ fluorocycloalkyl; R^(3a) is H,halo, OH, CN, C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ fluoroalkyl, C₁₋₃alkoxy, or C₃₋₆ cycloalkyl, wherein if V is —O—, —NR⁴—, —S—, —S(O)—,—SO₂—, or —C(═O)—, then R^(3a) is not halo, and wherein if V is —O—,—NR⁴—, —S—, then R^(3a) is not OH, CN; R^(3b) is H, ═O, C₁₋₃ alkyl, C₁₋₃hydroxyalkyl, C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, or C₃₋₆ cycloalkyl; R⁴ isH, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₂₋₃ hydroxyalkyl, CO₂R^(4a),C(O)R^(4a), SO₂R^(4a), C(O)N(R^(4b)R^(4b)), SO₂N(R^(4b)R^(4b)), or OH;R^(4a) is C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆fluorocycloalkyl, C₆₋₁₀ aryl or a 4 to 10 membered heterocycle having 1,2, 3 or 4 heteroatoms selected from O, S, and N, the aryl or heterocyclebeing substituted with 0-3 R^(4c); R^(4b) is independently H, C₁₋₃alkyl, C₂₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl, C₆₋₁₀aryl or a 4 to 10 membered heterocycle having 1, 2, 3 or 4 heteroatomsselected from O, S, and N; alternatively, 2 R^(4b)s, along with the atomto which they are attached, join to form a 3 to 6 membered saturatedring containing an additional 0-2 heteroatoms selected from O, S, and N;R^(4c) is independently H, F, Cl, or C₁₋₃ alkyl; R⁶ is independently H,OH, F, C₁₋₃ alkyl, C₁₋₃ deuteroalkyl, C₁₋₃ fluoroalkyl, C₃₋₆ cycloalkyl,C₃₋₆ fluorocycloalkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, C₁₋₃hydroxydeuteroalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃ fluoroalkoxyalkyl, orNR^(6b)R^(6b); wherein if one R⁶ on one carbon atom is F, OH orNR^(6b)R^(6b), then the other R⁶ on the same carbon atom is not OH orNR^(6b)R^(6b); R^(6b) is independently H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl,C(O)R^(a), SO₂R^(a) or C(O)NR^(b)R^(b); alternatively, 2 R⁶s along withthe same atom to which they are attached can form a 3 to 6 memberedsaturated ring containing 0-2 heteroatoms selected from O, S, and N;R^(a) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆ cycloalkyl,C₃₋₆ fluorocycloalkyl, C₆₋₁₀ aryl or a 4 to 10 membered heterocyclehaving 1, 2, 3, or 4 heteroatoms selected from O, S, and N; R^(b) isindependently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆ cycloalkyl, C₃₋₆fluorocycloalkyl, C₆₋₁₀ aryl or a 4 to 10 membered heterocycle having 1,2, 3 or 4 heteroatoms selected from O, S, and N; alternatively, 2R^(b)'s along with the atom to which they are attached, join to form a 3to 6 membered saturated ring, containing 0-2 heteroatoms selected fromO, S, and N; each R^(d) is independently H, F, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, C₁₋₃ hydroxyalkyl, C₃₋₆cycloalkyl, halo, OH, ═O, CN, OCF₃, OCHF₂, CHF₂CF₃, or C(O)NR^(e)R^(e);each R^(e) is independently H, C₁₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₆cycloalkyl, C₂₋₃ hydroxyalkyl, C₂₋₃ alkoxyalkyl, C₆₋₁₀ aryl, or a 5 to10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from O,S, and N; alternatively, 2 R^(e)s along with the atom to which they areattached, join to form a 3 to 6 membered saturated ring, containing 0-2heteroatoms selected from O, S, or N; and n is 0, 1, or
 2. 2. A compoundof claim 1, or salt thereof, wherein: R¹ is:

each R^(1a) is independently selected from F, Cl, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, and C₃₋₆ cycloalkyl; R^(1c) is independently H, deuterium,C₁₋₂ alkyl, or C₃₋₆ cycloalkyl; and n is zero, 1, or
 2. 3. A compound ofclaim 2, or salt thereof, wherein: R² is phenyl, pyridinyl, indolyl,indazolyl, benzo[d]oxazol-onyl, pyrazolo[4,3-b]pyridinyl,pyridin-2-onyl, pyrazolyl, [1,2,4]triazolo[1,5-a]pyridinyl,imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl,thiazolyl, thiophenyl, 1,2,3-triazolyl, benzo[d][1,2,3]triazolyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[d]imidazolyl, imidazolyl,pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl,pyrazolo[4,3-c]pyridinyl, pyrrolyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, tetrazolyl,1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridazinyl,pyrimidinyl, or benzo[d]oxazol-2-onyl, triazolyl, oxadiazolyl, orpyrrolopyridinyl, each being substituted with 0-3 R^(2a).
 4. A compoundof claim 3, or salt thereof, wherein: Ring B is pyridinyl, pyrimidinyl,pyrrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, isoxazolyl, pyrazinyl, oxazolyl, or pyridazinyl.
 5. Acompound of claim 4, or salt thereof, wherein: L¹ is —C(R)₂—, —C(O)—, or—CH₂—C(R)₂—; wherein R is independently from hydrogen, F, OH, C₁₋₃alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃fluoroalkyl.
 6. Acompound of claim 5, or salt thereof, wherein: R² is phenyl, pyridinyl,indolyl, indazolyl, benzo[d]oxazol-2(3H)-onyl, pyrazolo[4,3-b]pyridinyl,pyridin-2(1H)-onyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazolyl,triazolyl, oxadiazolyl, thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl,imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl,thiophenyl, [1,2,4]triazolo[4,3-b]pyridazinyl,pyrazolo[1,5-a]pyrimidinyl, or benzo[d]oxazol-2(3H)-only, each beingsubstituted with 0-3 R^(2a); R^(2a) is OH, ═O, CN, halo, SO₂C₁₋₄ alkyl,oxazolidin-2-one substituted with 0-1 R^(2b); and R^(2b) is C₁₋₃alkyl,C₁₋₃ fluoroalkyl, C₁₋₃ alkoxy, or C₁₋₃ fluoroalkoxy.
 7. A compound ofclaim 6, or salt thereof, wherein: R¹ is

R^(1a) is independently H or —CH₃.
 8. The compound according to claim 7,or salt thereof, wherein: Ring B is pyridinyl, triazolyl, thiazolyl,oxadiazolyl, imidazolyl, or pyrrazolyl; and R² is phenyl, pyridinyl,pyrimidinyl, benzo[d]oxazol-2(3H)-onyl, imidazolyl, pyrazolyl,triazolyl, or oxadiazolyl, each being substituted with 0-3 R^(2a). 9.The compound according to claim 8, or salt thereof, wherein: L¹ is—C(R)₂—; wherein R is independently hydrogen, F, OH, C₁₋₃ alkyl, C₁₋₃hydroxyalkyl, C₁₋₃ alkoxyalkyl, or C₁₋₃ fluoroalkyl; and R⁶ isindependently H, C₁₋₃-alkyl, C₁₋₃-fluoroalkyl, or C₃₋₆-cycloalkyl.
 10. Apharmaceutical composition comprising one or more compounds according toclaim 1, or a salt thereof; and a pharmaceutically acceptable carrier ordiluent.
 11. A pharmaceutical composition, which comprises apharmaceutically acceptable carrier and a compound as defined in claim1, or pharmaceutically acceptable salt, alone or in combination withanother therapeutic agent.
 12. A method for the treatment of acardiovascular disease, which comprises administering to a patienthaving said disease in need thereof a therapeutically affective amountof a compound of claim 1, or pharmaceutically acceptable salt thereof.13. The method of claim 12, wherein the cardiovascular disease isselected from hypertension, coronary heart disease, stroke, heartfailure, systolic heart failure, diastolic heart failure, diabetic heartfailure, acute-decompensated heart failure, post-operative volumeoverload, idiopathic edema, pulmonary hypertension, pulmonary arterialhypertension, cardiac insufficiency, nephrotic syndrome, and acutekidney insufficiency.
 14. A method for promoting diuresis ornatriuresis, which comprises administering to a patient in need thereofa therapeutically affective amount of a compound of claim 1, orpharmaceutically acceptable salt thereof.